Clinical trial NCT03582891: The Motor Network in Parkinson's Disease and Dystonia: Mechanisms of Therapy
Official title: Closed Loop Deep Brain Stimulation in Parkinson's Disease and Dystonia (Activa RC+S)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Parkinson Disease
Dystonia
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2018-07-11
Enrollment: 25
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Investigators will run a pilot clinical trial in which individualized classifier/control strategies for each hemisphere in each subject will be embedded within the RC+S for a total of one month (x4 one week blocks) of feedback-controlled stimulation will be compared with a total of one month of empirically optimized open-loop stimulation, (x4 one week blocks), administered in randomized order with adaptive stimulation. During these 1-month trials, patients and neurologists will be blinded to the state of the stimulator.
Primary purpose: TREATMENT

Brief summary: This is an exploratory pilot study to identify neural correlates of specific motor signs in Parkinson's disease (PD) and dystonia, using a novel totally implanted neural interface that senses brain activity as well as delivering therapeutic stimulation. Parkinson's disease and isolated dystonia patients will be implanted unilaterally or bilaterally with a totally internalized bidirectional neural interface, Medtronic Summit RC+S.

This study includes three populations: ten PD patients undergoing deep brain stimulation in the subthalamic nucleus (STN), ten PD patients with a globus pallidus (GPi) target and five dystonia patients. All groups will test a variety of strategies for feedback-controlled deep brain stimulation, and all patients will undergo a blinded, small pilot clinical trial of closed-loop stimulation for thirty days.

Detailed description: In this project investigators will develop adaptive DBS algorithms based on cortical and subcortical signals using the RC+S. This bidirectional neural interface is rechargeable (for up to 9 years of use), and is capable of delivering therapeutic open-loop stimulation or closed-loop stimulation. Its sensing capability includes four simultaneous time series channels at up to 1000 Hz sampling rate. In addition the device can stream time series data, and calculate and stream spectral power within a preset bandwidth. Twenty patients with idiopathic PD and motor fluctuations, or medically intractable tremor, will be implanted with unilateral or bilateral RC+S devices, each connected to a standard quadripolar DBS lead implanted in STN or globus pallidus, and to a 4-contact paddle type electrode placed subdurally over sensorimotor cortex. The basal ganglia lead will be used for both stimulation and LFP recordings, while the cortical lead will be used only for recording ECoG potentials, not for stimulation.

Patients with motor fluctuations cycle between a hypokinetic state (too little movement) and a hyperkinetic state (excessive movement). During open-loop DBS, brain state continues to fluctuate between these states and stimulation may induce dyskinesia or inadequately relieve akinesia.

With the goal of maintaining motor function within a normal range away from these two extremes, investigators will develop and test stimulation algorithms that utilize putative markers of both kinetic states. Investigators will also study neural signals of sleep and test stimulation to support specific sleep stages. The basic strategy is to automatically adjust stimulation parameters until the physiological signature of abnormal function is minimized. First, investigators will prototype adaptive stimulation paradigms and briefly (2 hours) test them in clinic, using a "distributed" configuration (streaming to a computer). Then, investigators will embed these algorithms in RC+S to test chronic and fully closed-loop DBS in a small double-blinded clinical trial. Investigators will pay careful attention to the possibility of progressive reduction in stimulation currents over the course of the study, which could support the hypothesis that "adaptive stimulation" might make the brain progressively less dependent on the device. In quantifying DBS amplitude and comparing open loop with adaptive stimulation, an important parameter is the total electrical energy delivered (TEED). TEED is calculated by the following equation as suggested by Koss and colleagues (TEED1sec = ((voltage2 x frequency x pulsewidth)/impedance) x 1sec). This can be used as measure of the energy saved when stimulation is delivered in closed-loop mode relative to empiric open-loop stimulation.

Eligibility criteria: Inclusion Criteria

Parkinson's Disease:

1. Ability to give informed consent for the study
2. Movement disorder symptoms that are sufficiently severe, in spite of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria
3. Patient has requested surgical intervention with deep brain stimulation for their disorder
4. No MR abnormalities that suggest an alternative diagnosis or contraindicate surgery
5. Absence of significant cognitive impairment (score of 20 or greater on the Montreal Cognitive Assessment (MoCA),
6. Signed informed consent
7. Ability to comply with study follow-up visits for brain recording, testing of adaptive stimulation, and clinical assessment.
8. Age 21-75 (for STN patients, minimum age is 25)
9. Diagnosis of idiopathic PD with duration of motor symptoms for 4 years or greater
10. Patient has undergone appropriate therapy with oral medications with inadequate relief as determined by a movement disorders neurologist, and has had stable doses of antiparkinsonian medications for 30 days prior to baseline assessment.
11. UPDRS-III score off medication between 20 and 80 and an improvement of at least 30% in the baseline UPDRS-III on medication score, compared to the baseline off-medication score, and motor fluctuations with at least 2 hours per day of on time without dyskinesia or with non-bothersome dyskinesia.

OR Patients with tremor-dominant PD (a tremor score of at least 2 on a UPDRS-III sub-score for tremor), treatment resistant, with significant functional disability despite maximal medical management

Dystonia:

1. Ability to give informed consent for the study
2. Movement disorder symptoms that are sufficiently severe, in spite of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria
3. Patient has requested surgical intervention with deep brain stimulation for their disorder
4. No MR abnormalities that suggest an alternative diagnosis or contraindicate surgery
5. Absence of significant cognitive impairment (score of 20 or greater on the Montreal Cognitive Assessment (MoCA)
6. Signed informed consent
7. Ability to comply with study follow-up visits for brain recording, testing of adaptive stimulation, and clinical assessment.
8. Age 21-75
9. Diagnosis of Isolated dystonia, which may be focal cervical, segmental craniocervical, or generalized forms.
10. Stable doses of anti-dystonia medications (such as trihexyphenydil, Baclofen, or clonazepam) for at least 30 days prior to baseline assessment
11. For dystonia patients with craniofacial and cervical involvement, prior treatment with botulinum toxin with failure to adequately control dystonia symptoms.

Exclusion Criteria

Parkinson's Disease:

1. Coagulopathy, anticoagulant medications, uncontrolled hypertension, history of seizures, heart disease, or other medical conditions considered to place the patient at elevated risk for surgical complications
2. Evidence of a psychogenic movement disorder: Motor symptoms that remit with suggestion or "while unobserved", symptoms that are inconsistent over time or incongruent with clinical condition, plus other manifestation such as "false" signs, multiple somatizations, or obvious psychiatric disturbance.
3. Pregnancy: all women of child bearing potential will have a negative urine pregnancy test prior to undergoing their surgical procedure.
4. Significant untreated depression (BDI-II score \>20) History of suicidal attempt or active suicidal ideation (Yes to #2-5 on C-SSRS)
5. Any personality or mood symptoms that study personnel believe will interfere with study requirements.
6. Subjects who require ECT, rTMS or diathermy
7. Implanted stimulation systems such as; cochlear implant, pacemaker, defibrillator, neurostimulator or metallic implant
8. Previous cranial surgery
9. Drug or alcohol abuse
10. Meets criteria for Parkinson's disease with mild cognitive impairment (PD-MCI). These criteria are: performance of more than two standard deviations below appropriate norms, for tests from two or more of these five cognitive domains: attention, executive function, language, memory, and visuospatial tests.

Dystonia:

1. Coagulopathy, anticoagulant medications, uncontrolled hypertension, history of seizures, heart disease, or other medical conditions considered to place the patient at elevated risk for surgical complications
2. Evidence of a psychogenic movement disorder: Motor symptoms that remit with suggestion or "while unobserved", symptoms that are inconsistent over time or incongruent with clinical condition, plus other manifestation such as "false" signs, multiple somatizations, or obvious psychiatric disturbance.
3. Pregnancy: all women of child bearing potential will have a negative urine pregnancy test prior to undergoing their surgical procedure.
4. Significant untreated depression (BDI-II score \>20) History of suicidal attempt or active suicidal ideation (Yes to #2-5 on C-SSRS)
5. Any personality or mood symptoms that study personnel believe will interfere with study requirements.
6. Subjects who require ECT, rTMS or diathermy
7. Implanted stimulation systems such as; cochlear implant, pacemaker, defibrillator, neurostimulator or metallic implant
8. Previous cranial surgery
9. Drug or alcohol abuse

Primary outcomes:
measure: Duration of 'on' stimulation time without dyskinesia from motor diaries in adaptive compared to standard open loop stimulation. (Parkinson's disease patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: The Burke-Fahn-Marsden Dystonia Rating Scale-Movement aDBS testing compared to pre-operative baseline(Dystonia Patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Toronto Western Spasmodic Torticollis Rating Scale during aDBS testing compared to pre-operative baseline (Dystonia Patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Karolinska Sleepiness Scale
timeFrame: Through study completion, up to 4 years
measure: Psychomotor vigilance task (PVT)
timeFrame: Through study completion, up to 4 years
measure: Positive and Negative Affect Schedule (PANAS-SF)
timeFrame: Through study completion, up to 4 years
Secondary outcomes:
measure: The Unified Parkinsons Disease Rating Scale (UPDRS) III scores off of medication in adaptive compared to standard open-loop stimulation. (Parkinson's disease patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Schwab England scale in adaptive compared to standard open loop stimulation. (Parkinson's disease patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Hoehn and Yahr Staging in the medication 'on' state in adaptive compared to standard open loop stimulation. (Parkinson's disease patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: The patient' quality of life report (PDQ-39) in adaptive compared to standard open loop stimulation. The PDQ39 yields a score between 0 to 100, where a higher score indicates more health problems. (Parkinson's disease patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Patient's Global Impression of Change (PGIC) in adaptive compared to standard open loop stimulation. (Parkinson's disease patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Total Electric Energy Delivered (TEED) by the pulse generator in adaptive compared to standard open loop stimulation. (all patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Short form 36 Quality of Life measure (Dystonia Patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Patient Global Impression of Change (Dystonia Patients)
timeFrame: Comparison will use data from the testing of open and closed-loop stimulation during chronic adaptive DBS testing at home.
measure: Resting state EEG Recording
timeFrame: Through study completion, up to 4 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Philip A Starr, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Powell MP, Anso J, Gilron R, Provenza NR, Allawala AB, Sliva DD, Bijanki KR, Oswalt D, Adkinson J, Pouratian N, Sheth SA, Goodman WK, Jones SR, Starr PA, Borton DA. NeuroDAC: an open-source arbitrary biosignal waveform generator. J Neural Eng. 2021 Feb 5;18(1):10.1088/1741-2552/abc7f0. doi: 10.1088/1741-2552/abc7f0.