Investigating the Use of Complex Pulse Shapes for DBS in Movement Disorders

Study Overview
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Brief Summary
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Parkinson's disease and essential tremor are chronic movement disorders for which there is no cure. When medication is no longer effective, deep brain stimulation (DBS) is recommended. Standard DBS is a neuromodulation method that uses a simple monophasic pulse, delivered from an electrode to stimulate neurons in a target brain area. This monophasic pulse spreads out from the electrode creating a broad, electric field that stimulates a large neural population. This can often effectively reduce motor symptoms. However, many DBS patients experience side effects - caused by stimulation of non-target neurons - and suboptimal symptom control - caused by inadequate stimulation of the correct neural target. The ability to carefully manipulate the stimulating electric field to target specific neural subpopulations could solve these problems and improve patient outcomes. The use of complex pulse shapes, specifically biphasic pulses and asymmetric pre-pulses, can control the temporal properties of the stimulation field. Evidence suggests that temporal manipulations of the stimulation field can exploit biophysical differences in neurons to target specific subpopulations. Therefore, our aim is to evaluate the effectiveness of complex pulse shapes to reduce side effects and improve symptom control in DBS movement patients.

Detailed Description
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The study had three stages. In the first stage, a wide range of investigatory pulse shapes in a small number of patients. The effect of the pulses on the therapeutic window will be assessed. Stage 2 will perform a short-term chronic evaluation in a larger number of patients of the complex pulse shape selected as most interesting from stage 1. ET patients will first be assessed after 3 hours of the cathodic or complex pulse (double-blind design). PD patients will only be assessed after 1 week of each pulse. Stage 3 will then focus on long-term evaluation (upto 2 years). Outcomes: see stage 2.

Official Title
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Investigating the Use of Complex Pulse Shapes for DBS in Movement Disorders

Conditions
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Parkinson Disease, Essential Tremor

Intervention / Treatment
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* Device: Boston Scientific: Study tool computer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for PD: Diagnosis of idiopathic Parkinson's disease where the diagnosis was made by a Movement Disorder Specialist according to the MDS criteria of 2015, with a Hoehn and Yahr scale (H&Y) of at least 2 (bilateral involvement). Onset of the symptoms more than five years ago. MDS-UPDRS-III score of ≥30 without medication or DBS. Electrodes are implanted in target area STN. Inclusion Criteria for ET: Patient is diagnosed with essential tremor by a Movement Disorder Specialist. Diagnosis since more than 3 years. Patient has a disabling medical-refractory upper extremity tremor without medication or DBS. Patient has a postural or kinetic tremor severity score of at least 3 out of 4 in the extremity intended for treatment on the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor without medication or DBS. Electrodes are implanted in target area VIM. General Inclusion Criteria: Post-op the implanted electrodes pass an integrity check, i.e. no open or shorted electrodes. Stable medications Lack of dementia or depression. Patient is willing and able to comply with all visits and study related procedures Patient understands the study requirements and the treatment procedures and provides written informed consent before any study-specific tests or procedures are performed. Patient can tolerate at least 12 hours OFF medication and per clinical judgement be able to perform all study related procedures Exclusion Criteria: Any significant psychiatric problems, including unrelated clinically significant depression. Any current drug or alcohol abuse. Any history of recurrent or unprovoked seizures. Have any significant medical condition that is likely to interfere with study procedures or likely to confound evaluation of study endpoints, including any terminal illness with survival <12 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, crossover, double-blinded design
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard clinical pulse shape<br>Standard clinical pulse shape as used in clinical practice (cathodic stimulation). | Device: Boston Scientific: Study tool computer<br>* compare clinical outcome measurements of complex pulse shapes to standard clinical pulse shape<br>|
| Experimental: Complex pulse shape<br>Complex pulse shape (i.e. biphasic pulse shape anode first, biphasic pulse shape cathode first, hyperpolarizing pre-pulse or depolarizing pre-pulse) | Device: Boston Scientific: Study tool computer<br>* compare clinical outcome measurements of complex pulse shapes to standard clinical pulse shape<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Therapeutic window = Amplitude at which therapeutic benefit is obtained versus amplitude at which side-effects occur, both expressed in mA (milliamperes). | Amplitude at which therapeutic benefit is obtained versus amplitude at which side-effects occur, both expressed in mA (milliamperes). | Immediately after testing | 
| Stage 2 ET (3 hours): tremor scores | FTM (Fahn-Tolosa-Marin) total score. Max 116 (higher score for more tremor). | Measured after 3 hours of stimulation | 
| Stage 2 ET (3 hours): ataxia scores | ICARS (International cooperative ataxia rating scale): total score. Max 100 (higher score for more ataxia). | Measured after 3 hours of stimulation | 
| Stage 2 ET (1 week): number of treatment-related adverse events as assessed by CTCAE v4.0 | Follow-up of (S)AE related to the study during that week | During 1 week of stimulation | 
| Stage 2 PD (1 week): number of treatment-related adverse events as assessed by CTCAE v4.0 | Follow-up of (S)AE related to the study during that week | During 1 week of stimulation | 
| Stage 3 ET (2 years): number of treatment-related adverse events as assessed by CTCAE v4.0 | Follow-up of (S)AE related to the study during those 2 years | During 2 years of stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Follow-up of (S)AE related to the study upto 1 week after the experiment | Upto one week after the study visit of stage 1 | 
| Stage 2 ET (3 hours): Therapeutic window: Amplitude to elicit tremor arrest, amplitude to elicit ataxia, amplitude to elicit stim-induced side-effects | Amplitude to elicit tremor arrest, amplitude to elicit ataxia, amplitude to elicit stimulation-induced side-effects (all expressed in mA) | Immediately after testing | 
| Stage 2 ET (3 hours): tremor subscores | FTM (Fahn-Tolosa-Marin) subscores: items 5, 6, 11, 12 and 13 (max 48, higher score for more tremor) | Measured at 1 hours, 2 hours and 3 hours after start of stimulation | 
| Stage 2 ET (3 hours): ataxia subscores | ICARS (international cooperative ataxia rating scale): item 10 (max 8, higher score for more ataxia) | Measured at 1 hours, 2 hours and 3 hours after start of stimulation | 
| Stage 2 ET (3 hours): speech assessment (least dysarthria) | Tests: sustained phonation /a/, diadochokinesis /tatata/, text reading and spontaneous speech Outcome: which of both pulses has less dysarthria per test (either cathodic pulse, either experimental pulse) | Measured at 1 hours, 2 hours and 3 hours after start of stimulation | 
| Stage 2 ET (1 week): tremor scores and subscores | FTM (Fahn-Tolosa-Marin) tremor rating scale: total score (max 116, higher score for more tremor) subscores: items 5, 6, 11, 12 and 13 (max 48, higher score for more tremor) | Measured after 1 week of stimulation | 
| Stage 2 ET (1 week): ataxia subscores and total score | ICARS (international cooperative ataxia rating scale): total score: max 100, higher score for more ataxia subscore: item 10 (max 8, higher score for more ataxia) | Measured after 1 week of stimulation | 
| Stage 2 ET (1 week): tremor measured with Kinesia One wearable | Amount of postural tremor and kinetic tremor in both hands (max 4 per side, higher score for more tremor) | Measured after 1 week of stimulation | 
| Stage 2 ET (1 week): tremor time measured with Kinesia 360 | Amount of tremor time measured with Kinesia 360 wearable (%, higher score for more tremor time) | Measured during 1 week of stimulation | 
| Stage 2 ET (1 week): speech assessment (least dysarthria) | Tests: sustained phonation /a/, diadochokinesis /tatata/, text reading and spontaneous speech Outcome: which of both pulses has less dysarthria per test (either cathodic pulse, either experimental pulse) | Measured after 1 week of stimulation | 
| Stage 2 ET (1 week): cognition | MoCA (Montreal Cognitive Assessment). Max 30, higher score for better cognition. | Measured after 1 week of stimulation | 
| Stage 2 ET (1 week): quality-of-life | QUEST (Quality-of-life in essential tremor questionnaire). Max 100%, higher score for worse quality-of-life. | Measured after 1 week of stimulation | 
| Stage 2 ET (1 week): quality-of-life | VAS (visual analogue scale) for: amount of tremor discomfort due to tremor Max 10, higher scores for worse outcome. | Measured once daily during 1 week of stimulation | 
| Stage 2 PD (1 week): therapeutic window (amplitude at loss of rigidity and amplitude at stim-induced side-effects) | Amplitude at loss of rigidity and amplitude at stimulation-induced side-effects | Immediately after testing | 
| Stage 2 PD (1 week): assessment motor symptoms in Parkinson's | MDS-UPDRS-III (Movement Disorders Society Unified Parkinson's Disease Rating Scale, part III). Max 132, higher score for more parkinsonian symptoms. | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): assessment non-motor symptoms in Parkinson's | NMSS (non-motor symptoms scale). Max 30, higher scores for more symptoms. | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): assessment of motor symptoms in Parkinson's with Kinesia One wearable | Wearable scores finger tapping and hand opening. Max 4 per item, higher scores for more symptoms. | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): assessment motor symptoms in Parkinson's with Kinesia 360 wearable | Wearable score amount of time that patient was bradykinetic and dyskinetic. Expressed as %, higher scores for more symptoms | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): assessment of speech (least dysarthria) | Tests: sustained phonation /a/, diadochokinesis /tatata/, text reading and spontaneous speech Outcome: which of both pulses has less dysarthria per test (either cathodic pulse, either experimental pulse) | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): cognition | MoCA (Montreal Cognitive Assessment). Max 30, higher score for better cognition. | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): quality-of-life | PDQ-39 (Parkinson's disease Questionnaire): 39-item questionnaire on quality-of-life. Expressed in %, higher score for more symptoms. | Measured after 1 week of stimulation | 
| Stage 2 PD (1 week): quality-of-life | VAS (visual analogue scale) for: amount of parkinsonian symptoms discomfort due to parkinsonian symptoms Max 10, higher scores for worse outcome. | Measured once daily during 1 week of stimulation |