Long-term Effect of Low Frequency Stimulation on Aspiration and Freezing of Gait in PD With STN DBS

Study Overview
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Brief Summary
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Our recent study (Xie et al, Neurology 2015; 84: 415-420) found that bilateral STN DBS of 60Hz, compared to the traditional 130Hz, decreased the aspiration frequency and swallowing difficulty, freezing of gait (FOG), and other axial symptoms and parkinsonism in Parkinson patients with FOG refractory to 130Hz and medications. The benefit of 60Hz stimulation persisted during the 6-week study period, but with worsening tremor in one patient. However, it remains unknown whether the benefit of 60Hz would persist on prolonged stimulation period, and whether there is carry-over effect across different conditions. Hence, the investigators would like to test the hypothesis that the 60Hz stimulation, compared to 130Hz might have persistent benefit over an extended period in reducing the swallowing dysfunction, FOG, and other axial symptoms in these PD patients even after correcting the potential carry-over effect.

Detailed Description
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The investigators will enroll 14 Parkinson patients with bilateral STN DBS and refractory FOG to 130Hz stimulation and dopaminergic medications for two visits of at least 6-month apart. The 6 patients remaining on 60Hz stimulation after our previous study consisting of 7 patients will be assessed once again as visit-2 after previous visit-1 of their last study. We anticipate to have 20 patents complete for visit-1 and at least 18 patients complete for visit-2 in this randomized double-blind prospective crossover study with their usual medication on state, with 6-7 patients on each starting condition (60Hz vs 130Hz vs DBS off). Swallowing function on modified barium swallowing test and swallowing questionnaire, FOG in stand-walk-sit test and questionnaire, and other axial and motor function on UPDRS-III will be assessed under each DBS condition. Changes in measurements between 60Hz and 130Hz at each visit and under 60Hz between two visits will be analyzed, with swallowing function and FOG as primary, and the rest as secondary outcomes, correcting for potential carryover effect. Changes between other DBS conditions might also be explored in this 2-year study. This would be the first study on the long-term effect of 60Hz stimulation on dysphagia, FOG and other axial and motor symptoms in Parkinson patients with bilateral STN DBS and FOG refractory to 130Hz stimulation and dopaminergic medications, which will have significant impact on the treatment of difficult axial symptoms of high morbidity and mortality.

Official Title
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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

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Device: Deep Brain Stimulation (DBS) at 60 Hz
* Device: Deep Brain Stimulation (DBS) at 130 Hz
* Device: Deep Brain Stimulation (DBS) Off (Sham)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PD patients with bilateral STN DBS placement and FOG at 130Hz even at usual medication on state. Exclusion Criteria: Known history of recent aspiration pneumonia

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deep Brain Stimulation (DBS)<br>All patients were treated and assessed under three conditions (60 Hz DBS, 130 Hz DBS and no DBS) at Visit 1 (V1), were then treated with 60 Hz DBS for at least 6 months (14.5 months on average), and were finally reassessed during a second visit (V2) under the same three conditions as V1. The order of treatment/assessment under the three conditions was randomized at each visit. | Device: Deep Brain Stimulation (DBS) at 60 Hz<br>* Bilateral subthalamic nucleus deep brain stimulation at 60 Hz<br>* Other names: Low Frequency Stimulation (LFS);Device: Deep Brain Stimulation (DBS) at 130 Hz<br>* Bilateral subthalamic nucleus deep brain stimulation at 130 Hz<br>* Other names: High Frequency Stimulation (HFS);Device: Deep Brain Stimulation (DBS) Off (Sham)<br>* Deep Brain Stimulation (DBS) Off (Sham)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Aspiration Events on Videofluoroscopic Swallow Study at Visit 1 | A speech pathologist used the Penetration-Aspiration Scale (PAS) to rate swallows captured by a radiologist during VFSS recording. PAS is an 8-point interval scale: a score of 0 indicates no penetration or aspiration & a score of 6-8 indicates aspiration of increasing severity. For the purpose of this study, aspiration was dichotomized to 0 if PAS score was under 6 or 1 if PAS score was between 6-8. Frequency of aspiration events was calculated by adding number of aspiration events in VFSS under various liquid & food textures. The maximum aspiration frequency was 12 if aspiration occurred on every texture after 2 trials. Lower aspiration frequency means better swallowing function. | Immediately following treatment for at least 30 minutes | 
| Perceived Swallowing Difficulty on Swallowing Disturbance Questionnaire at Visit 1 | The Swallowing Disturbance Questionnaire contains 15 items. Each item has 4-points ranging from 0 (absence of symptoms) to 3 (severe or very frequent). Total score ranges from 0-45, with higher scores corresponding to more severe swallowing disturbance. | Immediately following treatment for at least 30 minutes | 
| Freezing of Gait Questionnaire at Visit 1 | The Freezing of Gait (FOG) Questionnaire contains 6 items to evaluate the severity of FOG in patients with Parkinson's disease. Each item has 5 points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-24, with higher scores corresponding to more severe FOG. | Immediately following treatment for at least 30 minutes | 
| Stand-Walk-Sit Freezing of Gait Spells at Visit 1 | The Stand-Walk-Sit (SWS) Test assesses freezing of gait (FOG) spells observed when standing up, walking 7 meters, and returning to a seated position. The greater the number of FOG spells counted, the worse the FOG symptoms. | Immediately following treatment for at least 30 minutes | 
| Stand-Walk-Sit Time at Visit 1 | Stand-Walk-Sit (SWS) Time measures the total time taken to complete the SWS test of standing up, walking 7 meters, and returning to a sitting position. The longer time (in seconds) it took to complete the SWS test, the worse the FOG symptoms. | Immediately following treatment for at least 30 minutes | 
| Frequency of Aspiration Events on Videofluoroscopic Swallow Study at Visit 2 | A speech pathologist used the Penetration-Aspiration Scale (PAS) to rate swallows captured by a radiologist during VFSS recording. PAS is an 8-point interval scale: a score of 0 indicates no penetration or aspiration & a score of 6-8 indicates aspiration of increasing severity. For the purpose of this study, aspiration was dichotomized to 0 if PAS score was under 6 or 1 if PAS score was between 6-8. Frequency of aspiration events was calculated by adding number of aspiration events in VFSS under various liquid & food textures. The maximum aspiration frequency was 12 if aspiration occurred on every texture after 2 trials. Lower aspiration frequency means better swallowing function. | Immediately following treatment for at least 30 minutes | 
| Perceived Swallowing Difficulty on Swallowing Disturbance Questionnaire at Visit 2 | The Swallowing Disturbance Questionnaire contains 15 items. Each item has 4-points ranging from 0 (absence of symptoms) to 3 (severe or very frequent). Total score ranges from 0-45, with higher scores corresponding to more severe swallowing disturbance. | Immediately following treatment for at least 30 minutes | 
| Freezing of Gait Questionnaire at Visit 2 | The Freezing of Gait (FOG) Questionnaire contains 6 items to evaluate the severity of FOG in patients with Parkinson's disease. Each item has 5 points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-24, with higher scores corresponding to more severe FOG. | Immediately following treatment for at least 30 minutes | 
| Stand-Walk-Sit Freezing of Gait Spells at Visit 2 | The Stand-Walk-Sit (SWS) Test assesses freezing of gait (FOG) spells observed when standing up, walking 7 meters, and returning to a seated position. The greater the number of FOG spells counted, the worse the FOG symptoms. | Immediately following treatment for at least 30 minutes | 
| Stand-Walk-Sit Time at Visit 2 | Stand-Walk-Sit (SWS) Time measures the total time taken to complete the SWS test of standing up, walking 7 meters, and returning to a sitting position. The longer time (in seconds) it took to complete the SWS test, the worse the FOG symptoms. | Immediately following treatment for at least 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unified Parkinson's Disease Rating Scale-III Total Score at Visit 1 | Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 33 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-132, with higher scores corresponding to more severe parkinsonism. | Immediately following treatment for at least 30 minutes | 
| Axial Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 1 | The axial subscore of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 7 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-28, with higher scores corresponding to more severe axial symptoms. Specifically, axial symptoms include: speech, facial expression, arising from chair, gait, freezing of gait, postural stability, posture. | Immediately following treatment for at least 30 minutes | 
| Bradykinesia Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 1 | The bradykinesia subscore of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 11 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-44, with higher scores corresponding to more severe bradykinesia. Specifically, bradykinesia symptoms include: finger tapping right hand, finger tapping left hand, hand movements right hand, hand movements left hand, pronation-supination movements right hand, pronation- supination movements left hand, toe tapping right foot, toe tapping left foot, leg agility right leg, leg agility left leg, global spontaneity of movement. | Immediately following treatment for at least 30 minutes | 
| Rigidity Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 1 | The rigidity subscore of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 5 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-20. with higher scores corresponding to more severe rigidity. Specifically, rigidity symptoms include: rigidity neck, rigidity right upper extremity, rigidity left upper extremity, rigidity right lower extremity, rigidity left lower extremity. | Immediately following treatment for at least 30 minutes | 
| Tremor Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 1 | The tremor subscore of Unified Parkinson's Disease Rating Scale (UPDRS-III) contains 10 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-40, with higher scores corresponding to more severe tremor. Specifically, tremor symptoms include: postural tremor right hand, postural tremor left hand, kinetic tremor right hand, kinetic tremor left hand, rest tremor amplitude right upper extremity, rest tremor amplitude left upper extremity, rest tremor amplitude right lower extremity, rest tremor amplitude left lower extremity, rest tremor amplitude lip/jaw, constancy of rest tremor. | Immediately following treatment for at least 30 minutes | 
| Unified Parkinson's Disease Rating Scale-III Total Score at Visit 2 | Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 33 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-132, with higher scores corresponding to more severe parkinsonism. | Immediately following treatment for at least 30 minutes | 
| Axial Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 2 | The axial subscore of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 7 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-28, with higher scores corresponding to more severe axial symptoms. Specifically, axial symptoms include: speech, facial expression, arising from chair, gait, freezing of gait, postural stability, posture. | Immediately following treatment for at least 30 minutes | 
| Bradykinesia Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 2 | The bradykinesia subscore of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 11 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-44, with higher scores corresponding to more severe bradykinesia. Specifically, bradykinesia symptoms include: finger tapping right hand, finger tapping left hand, hand movements right hand, hand movements left hand, pronation-supination movements right hand, pronation- supination movements left hand, toe tapping right foot, toe tapping left foot, leg agility right leg, leg agility left leg, global spontaneity of movement. | Immediately following treatment for at least 30 minutes | 
| Rigidity Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 2 | The rigidity subscore of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) contains 5 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-20. with higher scores corresponding to more severe rigidity. Specifically, rigidity symptoms include: rigidity neck, rigidity right upper extremity, rigidity left upper extremity, rigidity right lower extremity, rigidity left lower extremity. | Immediately following treatment for at least 30 minutes | 
| Tremor Subscore of Unified Parkinson's Disease Rating Scale-III at Visit 2 | The tremor subscore of Unified Parkinson's Disease Rating Scale (UPDRS-III) contains 10 items. Each item has 5-points ranging from 0 (absence of symptoms) to 4 (severe). Total score ranges from 0-40, with higher scores corresponding to more severe tremor. Specifically, tremor symptoms include: postural tremor right hand, postural tremor left hand, kinetic tremor right hand, kinetic tremor left hand, rest tremor amplitude right upper extremity, rest tremor amplitude left upper extremity, rest tremor amplitude right lower extremity, rest tremor amplitude left lower extremity, rest tremor amplitude lip/jaw, constancy of rest tremor. | Immediately following treatment for at least 30 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Freezing of gait, DBS, Low frequency stimulation, Dysphagia