Parkinson's Disease
Conditions
Brief summary
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Scale (UPDRS III) and specific phenotypic measures in Parkinson's Disease compared to OFF therapy (i.e., OFF DBS and withdrawn from medication) and more efficient than cDBS.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.
Interventions
DEVICEAdaptive DBS (Activa PC+S Neurostimulator)
DEVICEContinuous DBS (Activa PC+S Neurostimulator)
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. A diagnosis of idiopathic Parkinson's disease, with bilateral symptoms at Hoehn and Yahr Stage greater than or equal to II. 2. 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. 3. 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. 4. 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. 5. Treatment with carbidopa/levodopa, and with a dopamine agonist at the maximal tolerated doses as determined by a movement disorders neurologist. 6. Ability and willingness to return for study visits, at the initial programming and after three, six and twelve months of DBS. 7. Age \> 18
Exclusion criteria
1. Subjects with significant cognitive impairment and/or dementia as determined by a standardized neuropsychological battery. 2. 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. 3. Subjects with very advanced Parkinson's disease, Hoehn and Yahr stage 5 on medication (non-ambulatory). 4. Age \> 80. 5. Subjects with an implanted electronic device such as a neurostimulator, cardiac pacemaker/defibrillator or medication pump. 6. Subjects, who are pregnant, are capable of becoming pregnant, or who are breast feeding. 7. 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 8. Subjects having a major comorbidity increasing the risk of surgery (prior stroke, severe hypertension, severe diabetes, or need for chronic anticoagulation other than aspirin). 9. Subjects having any prior intracranial surgery. 10. Subjects with a history of seizures. 11. Subjects, who are immunocompromised. 12. Subjects with an active infection. 13. Subjects, who require diathermy, electroconvulsive therapy (ECT), or transcranial magnetic stimulation (TMS) to treat a chronic condition. 14. Subjects, who have an inability to comply with study follow-up visits. 15. Subjects, who are unable to understand or sign the informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalized Beta Band Power (13-30 Hz) During aDBS | 30 minutes | 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. |
| Change in UPDRS III Score | 30 minutes | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Symptoms (Bradykinesia) | 30 minutes | 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. |
| Disease Symptoms (Tremor) | 30 minutes | 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. |
| Disease Symptoms (Freezing of Gait) | 30 minutes | Percent time freezing during a stepping-in-place task. Higher percent time freezing represents a worse outcome. |
| DBS Voltage | 30 minutes | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Activa PC+S Neurostimulator Participants will be own controls and undergo both Adaptive DBS and Continuous DBS deep brain stimulation | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Activa PC+S Neurostimulator |
|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Mean OFF UPDRS-III at Initial Programming | 41.9 UPDRS-III Score STANDARD_DEVIATION 15.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 22 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 22 |
| other Total, other adverse events | 20 / 22 |
| serious Total, serious adverse events | 4 / 22 |
Outcome results
Primary
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.
Time frame: 30 minutes
Population: Participants who were assessed for this outcome (had a clinical UPDRS assessment).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Activa PC+S Neurostimulator | Change in UPDRS III Score | OFF | 28.1 score on a scale | Standard Deviation 17.1 |
| Activa PC+S Neurostimulator | Change in UPDRS III Score | aDBS | 12.5 score on a scale | Standard Deviation 10.5 |
p-value: 0.0064t-test, 2 sided
Primary
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.
Time frame: 30 minutes
Population: Participants who were assessed for this outcome and with no artifacts in the local field potential signal.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Activa PC+S Neurostimulator | Normalized Beta Band Power (13-30 Hz) During aDBS | 0.26 Normalized median beta power | Standard Deviation 0.14 |
p-value: <0.001t-test, 2 sided
Secondary
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.
Time frame: 30 minutes
Population: Participants who were assessed for this outcome and with no artifacts in the local field potential signal.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Activa PC+S Neurostimulator | DBS Voltage | Clinical Open Loop (cDBS) | 3.12 median stimulation voltage | Standard Deviation 0.54 |
| Activa PC+S Neurostimulator | DBS Voltage | aDBS | 2.03 median stimulation voltage | Standard Deviation 0.91 |
p-value: <0.001t-test, 2 sided
Secondary
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.
Time frame: 30 minutes
Population: Participants who were assessed for this outcome and with no artifacts in the local field potential signal, substantial tremor in the tested limb, or technical issues during the kinematic recording.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Activa PC+S Neurostimulator | Disease Symptoms (Bradykinesia) | OFF | 352.58 root mean squared of angular velocity | Standard Deviation 56.46 |
| Activa PC+S Neurostimulator | Disease Symptoms (Bradykinesia) | aDBS | 457.44 root mean squared of angular velocity | Standard Deviation 58.96 |
p-value: 0.003t-test, 2 sided
Secondary
Disease Symptoms (Freezing of Gait)
Percent time freezing during a stepping-in-place task. Higher percent time freezing represents a worse outcome.
Time frame: 30 minutes
Population: Participants who were assessed for this outcome and with no artifacts in the local field potential signal, artifacts in the kinematic data, or excluded since they did not identify as freezers.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Activa PC+S Neurostimulator | Disease Symptoms (Freezing of Gait) | aDBS | 0 percentage of time freezing | Standard Deviation 1 |
| Activa PC+S Neurostimulator | Disease Symptoms (Freezing of Gait) | OFF | 22 percentage of time freezing | Standard Deviation 30 |
p-value: 0.25Wilcoxon Signed-Rank Test
Secondary
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.
Time frame: 30 minutes
Population: Participants who were assessed for this outcome and not excluded due to lack of tremor.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Activa PC+S Neurostimulator | Disease Symptoms (Tremor) | OFF | 0.040 (rad/s)^2 | Standard Deviation 0.11 |
| Activa PC+S Neurostimulator | Disease Symptoms (Tremor) | aDBS | 0.0072 (rad/s)^2 | Standard Deviation 0.018 |
p-value: 0.014t-test, 2 sided