Adaptive Closed Loop Neuromodulation and Neural Signatures of Parkinson's Disease

Study Overview
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Brief Summary
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Continuous deep brain stimulation (cDBS) is an established therapy for the major motor signs in Parkinson's disease. Currently, cDBS is limited to open-loop stimulation, without real-time adjustment to the patient's state of activity, fluctuations and types of motor symptoms, medication dosages, or neural markers of the disease. The purpose of this study is to determine if an adaptive DBS system, responding to patient specific, clinically relevant neural or kinematic feedback, is efficacious on the motor Unified Parkinson's Disease Rating Scale (UPDRS III) and specific phenotypic measures in Parkinson's Disease compared to OFF therapy (i.e., OFF DBS and withdrawn from medication) and more efficient than cDBS. Not every recruited participant completed every part of the protocol.

Official Title
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Adaptive Closed Loop Neuromodulation and Neural Signatures of Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Device: Adaptive DBS (Activa PC+S Neurostimulator)
* Device: Continuous DBS (Activa PC+S Neurostimulator)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of idiopathic Parkinson's disease, with bilateral symptoms at Hoehn and Yahr Stage greater than or equal to II. Documented improvement in motor signs on versus off dopaminergic medication, with a change in the Unified Parkinson's Disease Rating Scale motor (UPDRS III) score of >= 30% off to on medication. The presence of complications of medication such as wearing off signs, fluctuating responses and/or dyskinesias, and/or medication refractory tremor, and/or impairment in the quality of life on or off medication due to these factors. Subjects should be on stable doses of medications, which should remain unchanged until the DBS system is activated. After the DBS system is optimized (during which time the overall medication dose may be reduced to avoid discomfort and complications such as dyskinesias) the medication dose should remain unchanged, if possible, for the duration of the study. Treatment with carbidopa/levodopa, and with a dopamine agonist at the maximal tolerated doses as determined by a movement disorders neurologist. Ability and willingness to return for study visits, at the initial programming and after three, six and twelve months of DBS. Age > 18 Exclusion Criteria: Subjects with significant cognitive impairment and/or dementia as determined by a standardized neuropsychological battery. Subjects with clinically active depression, defined according to the Diagnostic and Statistical manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and as scored on a validated depression assessment scale. Subjects with very advanced Parkinson's disease, Hoehn and Yahr stage 5 on medication (non-ambulatory). Age > 80. Subjects with an implanted electronic device such as a neurostimulator, cardiac pacemaker/defibrillator or medication pump. Subjects, who are pregnant, are capable of becoming pregnant, or who are breast feeding. Patients with cortical atrophy out of proportion to age or focal brain lesions that could indicate a non-idiopathic movement disorder as determined by MRI Subjects having a major comorbidity increasing the risk of surgery (prior stroke, severe hypertension, severe diabetes, or need for chronic anticoagulation other than aspirin). Subjects having any prior intracranial surgery. Subjects with a history of seizures. Subjects, who are immunocompromised. Subjects with an active infection. Subjects, who require diathermy, electroconvulsive therapy (ECT), or transcranial magnetic stimulation (TMS) to treat a chronic condition. Subjects, who have an inability to comply with study follow-up visits. Subjects, who are unable to understand or sign the informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Activa PC+S Neurostimulator<br>Participants will be own controls and undergo both adaptive and continuous deep brain stimulation testing paradigms using Nexus D research tool PC+S: Primary Cell+Sensing | Device: Adaptive DBS (Activa PC+S Neurostimulator)<br> <br> * Other names: Adaptive deep brain stimulation;Device: Continuous DBS (Activa PC+S Neurostimulator)<br> <br> * Other names: continuous deep brain stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalized Beta Band Power (13-30 Hz) During aDBS | Beta Band Power will be recorded continuously during intervention (30 minutes). The PC+S streams off power of the local field potential signal measured from the subthalamic nucleus in a frequency band of interest within the beta band (13-30 Hz). The amplitude of the signal, beta power, was streamed from each subthalamic nucleus (STN) during the calibration period of the experiment when DBS was off (i.e., OFF therapy), when continuous DBS was set at the lower and upper stimulation voltage that were found for determining the stimulation limits of adaptive DBS, and during the 30 minutes of aDBS. We calculated the median observed beta power during aDBS. To compute normalized beta band power, the median value was divided by the observed beta power OFF therapy and during the continuous DBS at the lower and upper voltage. A value less than 1 indicates reduced beta power during aDBS compared to the other conditions. | 30 minutes | 
| Change in UPDRS III Score | Movement Disorder Society's Unified Parkinson's Disease Rating Scale III (UPDRS III) score will be measured after 30 minutes of intervention and compared to baseline. Scores on the UPDRS III range from 0-132. Higher scores represent a worse outcome. For some participants, a modified UPDRS III was used in which items 3.9, 3.10, 3.11, 3.12, and 3.13 were excluded to only focus on the seated portion of the assessment, or only one hemibody was tested if the aDBS controller was only controlling one subthalamic nucleus. | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Symptoms (Tremor) | Mean tremor power calculated from a triaxial gyroscope using a fast Fourier transform averaged between 4 and 8 Hz. Higher tremor power indicates worse tremor. | 30 minutes | 
| Disease Symptoms (Freezing of Gait) | Percent time freezing during a stepping-in-place task. Higher percent time freezing represents a worse outcome. | 30 minutes | 
| Disease Symptoms (Bradykinesia) | The root mean squared of the angular velocity during a wrist-flexion extension task. Higher root mean squared of angular velocity represents a better outcome. | 30 minutes | 
| DBS Voltage | The median stimulation voltage during the aDBS run was determined for each individual's subthalamic nucleus. The overall group mean of the median stimulation voltages was compared to the group mean of the clinical continuous DBS (cDBS) median voltages. | 30 minutes |