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The study will test the feasibility of using Low Intensity Focused Ultrasound Pulsation (LIFUP) to treat motor symptoms in Parkinson's Disease (PD). LIFUP is a new technique that can increase brain activity in highly specific target areas and is MRI compatible. Thus, in real-time, it is possible to directly observe how LIFUP changes the brain areas important in PD by measuring its effects on brain activity, blood flow, and brain connectivity. If successful, this research will mark the first step towards a novel, non-invasive, non-medication treatment for PD.
This trial is a proof-of-concept, proof-of-mechanism study of a novel neuromodulation technology - LIFUP - to treat motor symptoms in PD. Much like Deep Brain Stimulation, LIFUP can be focused on deep brain structures with high spatial accuracy, including those implicated in PD; however, it can do so non-invasively. Other non-invasive neuromodulation tools such as Transcranial Magnetic Stimulation can only target surface brain structures and are not optimal PD treatment tools. This study will test this new technology in 30 participants with PD during simultaneous resting state functional MRI, and collect pre- and post-LIFUP functional MRI, arterial spin labeling, motor performance data, and behavioral data, in a double-blind crossover trial to determine whether LIFUP: 1) will improve motor symptoms during and after treatment; 2) can modulate neural activity in the target brain region important for PD, the internal globus pallidus; and 3) enhance cortico-striatal motor circuit connectivity. All participants in this study will receive active ultrasound at one of the two in-person sessions and sham at the other.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active, then Sham | Experimental | Active Low intensity focused ultrasound pulsation (LIFUP) will be administered to the internal globus pallidus while participants are in the MRI scanner. Then, 2 weeks later, sham LIFUP will be administered. |
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| Sham, then Active | Experimental | Sham low intensity focused ultrasound pulsation (LIFUP) will be administered while participants are in the MRI scanner. Then, 2 weeks later, active LIFUP will be administered to the internal globus pallidus. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active LIFUP Treatment | Device | Low intensity focused ultrasound pulsation will be administered to the internal globus pallidus in 20 sonications at 650kHz, ispta.3 720mW/cm, pulse repetition frequency 100Hz, duty cycle 5%, duration 30s with 30s spacing between sonications. For active LIFUP, the device will be used with a gel pad that allows the ultrasound to pass through. |
| Measure | Description | Time Frame |
|---|---|---|
| Motor Assessment 1: Unified Parkinson Disease Rating Scale (UPDRS) Section 3 | The participant will complete a 18-item comprehensive motor assessment that assesses elements of motor function including tremor, bradykinesia, and gait. The total score for this assessment ranges from 0 to 108 points, with higher scores indicating higher severity. | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
| Motor Assessment 2: Finger Tapping (Score) | This task, which is item 3.4 on the Unified Parkinson's Disease Rating Scale (UPDRS), asks participants to tap their index finger on their thumb ten times as big and as fast as possible. Participants scores on item 3.4 with standard UPDRS scoring criteria (on a scale of 0 to 4, where a higher score indicates more severe Parkinson's symptoms i.e. worse performance) will be assessed pre and post-LIFUP. The scores reported below are for the hand on the side with worse symptoms (i.e. the side that LIFUP is intended to primarily affect). | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
| Motor Assessment 2: Finger Tapping (Speed) | This task, which is item 3.4 on the Unified Parkinson's Disease Rating Scale (UPDRS), asks participants to tap their index finger on their thumb ten times as big and as fast as possible. The speed of taps will be assessed pre and post-LIFUP. Speed is calculated as [number of taps per second] times [average tap amplitude], where tap amplitude is measured on a scale of 0.0-1.0 representing the percentage of finger extension between taps, where e.g. extension to a 90 degree angle between thumb and index finger = 1.0, extension to 45 degree angle = 0.5, etc. Higher speed indicates better performance. The speed values reported below are for the hand on the side with worse symptoms (i.e. the side that LIFUP is intended to primarily affect). | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
| Motor Assessment 2: 9-Hole Pegboard Dexterity Test | The participant will place and remove nine plastic pegs into a plastic pegboard. Scores are recorded as time in seconds that it takes the participant to complete the task with each hand. Analysis will compare pre- and post-treatment scores to quantify motor performance improvements. |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in BOLD fMRI Signal Between on vs. Off Blocks | BOLD data will be collected in real-time during the ultrasound sonication, which occurs in interleaved 30 second "on" and "off" blocks. Analyses will assess the statistical relationship between BOLD signal in the brain and the time series (on vs off) of the ultrasound sonication. Tabular data reported here represents the difference in BOLD activation between on and off conditions in the internal globus pallidus on the targeted side of the brain, calculated as the mean BOLD activation while LIFUP is on minus mean activation when it is off. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Susan Y Bookheimer, Ph.D. | University of California, Los Angeles | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Los Angeles | Los Angeles | California | 90095 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Active, Then Sham | Active Low intensity focused ultrasound pulsation (LIFUP) will be administered to the internal globus pallidus while participants are in the MRI scanner. Then, 2 weeks later, sham LIFUP will be administered. Active LIFUP Treatment: Low intensity focused ultrasound pulsation will be administered to the internal globus pallidus in 20 sonications at 650kHz, ispta.3 720mW/cm, pulse repetition frequency 100Hz, duty cycle 5%, duration 30s with 30s spacing between sonications. For active LIFUP, the device will be used with a gel pad that allows the ultrasound to pass through. Sham LIFUP Treatment: The device will be aimed at the internal globus pallidus and turned on with the same settings as the active condition; however, in this case, the device will be used with a gel pad that blocks the ultrasound from passing through, such that no ultrasound is actually being administered to the brain. |
| FG001 | Sham, Then Active | Sham low intensity focused ultrasound pulsation (LIFUP) will be administered while participants are in the MRI scanner. Then, 2 weeks later, active LIFUP will be administered to the internal globus pallidus. Active LIFUP Treatment: Low intensity focused ultrasound pulsation will be administered to the internal globus pallidus in 20 sonications at 650kHz, ispta.3 720mW/cm, pulse repetition frequency 100Hz, duty cycle 5%, duration 30s with 30s spacing between sonications. For active LIFUP, the device will be used with a gel pad that allows the ultrasound to pass through. Sham LIFUP Treatment: The device will be aimed at the internal globus pallidus and turned on with the same settings as the active condition; however, in this case, the device will be used with a gel pad that blocks the ultrasound from passing through, such that no ultrasound is actually being administered to the brain. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (1 day) |
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| Washout / Follow-Up (2 weeks) |
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| Second Intervention (1 day) |
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| Second Intervention Follow-Up (1 week) |
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One participant in the "sham then active" group was withdrawn after their first in-person session due to excessive head motion in the MRI.
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| ID | Title | Description |
|---|---|---|
| BG000 | Active, Then Sham | Active Low intensity focused ultrasound pulsation (LIFUP) will be administered to the internal globus pallidus while participants are in the MRI scanner. Then, 2 weeks later, sham LIFUP will be administered. Active LIFUP Treatment: Low intensity focused ultrasound pulsation will be administered to the internal globus pallidus in 20 sonications at 650kHz, ispta.3 720mW/cm, pulse repetition frequency 100Hz, duty cycle 5%, duration 30s with 30s spacing between sonications. For active LIFUP, the device will be used with a gel pad that allows the ultrasound to pass through. Sham LIFUP Treatment: The device will be aimed at the internal globus pallidus and turned on with the same settings as the active condition; however, in this case, the device will be used with a gel pad that blocks the ultrasound from passing through, such that no ultrasound is actually being administered to the brain. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Motor Assessment 1: Unified Parkinson Disease Rating Scale (UPDRS) Section 3 | The participant will complete a 18-item comprehensive motor assessment that assesses elements of motor function including tremor, bradykinesia, and gait. The total score for this assessment ranges from 0 to 108 points, with higher scores indicating higher severity. | One participant was not included in motor symptom analyses due to extreme motor symptom fluctuations at baseline confounding measurement of LIFUP-related changes | Posted | Mean | Standard Deviation | score on a scale | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
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Adverse event data were collected 2, 4, and 7 days after each in-person session, and the two in-person sessions were two weeks apart. As a result, depending on whether participants received active then sham or sham then active, adverse event data were collected for either one week or three weeks after the active intervention.
Participants were asked a series of open-ended questions 2, 4, and 7 days after each in-person sessions, as well as at the start of their second in person session (i.e. 2 weeks after session 1) . These questions asked participants if they had observed any 1. changes in impulsivity, anxiety, mood, or thinking skills, 2. motor changes, and 3. other changes, as well as if they had any other comments.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active LIFUP Session | LIFUP will be administered to the internal globus pallidus on the side of the brain contralateral to the side of the body with worse symptoms. The side of the brain contralateral to worse symptoms is being targeted because the left hemisphere of the brain primarily controls right side motor function and vice versa. The LIFUP protocol will entail 20 sonications at 650kHz, 720mW/cm, duty cycle 5%, pulse repetition frequency 100Hz, duration 30s, with 30s spacing between sonications. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Head or Neck Pain | Nervous system disorders | Systematic Assessment | Participants reporting headache, neck pain, or local pain on scalp at site of device during or after LIFUP or sham procedure |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Natalie Rotstein | University of California Los Angeles | 310-794-0077 | tfus@mednet.ucla.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 16, 2022 | Nov 17, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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Participants will be assigned to both study arms; the order in which they complete the arms will be randomized and counterbalanced. The two visits will be spaced apart by 2 weeks.
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All participants complete two identical in-person testing and LIFUP sessions. At one session, the device will be used with a gel pad that allows ultrasound to pass through, and at the other session, it will be used with a gel pad that blocks the ultrasound. The order of conditions is randomized and counterbalanced across participants. The two gel pads look identical beyond a label differentiating them, and neither the participants nor the person administering ultrasound will know whether sham or active is being administered at a given session.
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| Sham LIFUP Treatment | Device | The device will be aimed at the internal globus pallidus and turned on with the same settings as the active condition; however, in this case, the device will be used with a gel pad that blocks the ultrasound from passing through, such that no ultrasound is actually being administered to the brain. |
|
| Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
| During LIFUP (or sham) sonication on Day 1 and Day 15 |
| Perfusion Changes in Internal Globus Pallidus, External Globus Pallidus, and Putamen | Arterial spin labeling data will be collected before and after sonication. Analyses will assess the statistical relationship between perfusion in the targeted internal globus pallidus, external globus pallidus, and putamen pre- and post-sonication in a within-subject repeated measures design. | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
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| BG001 | Sham, Then Active | Sham low intensity focused ultrasound pulsation (LIFUP) will be administered while participants are in the MRI scanner. Then, 2 weeks later, active LIFUP will be administered to the internal globus pallidus. Active LIFUP Treatment: Low intensity focused ultrasound pulsation will be administered to the internal globus pallidus in 20 sonications at 650kHz, ispta.3 720mW/cm, pulse repetition frequency 100Hz, duty cycle 5%, duration 30s with 30s spacing between sonications. For active LIFUP, the device will be used with a gel pad that allows the ultrasound to pass through. Sham LIFUP Treatment: The device will be aimed at the internal globus pallidus and turned on with the same settings as the active condition; however, in this case, the device will be used with a gel pad that blocks the ultrasound from passing through, such that no ultrasound is actually being administered to the brain. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| OG001 | Sham LIFUP Session | LIFUP will be administered with an identical protocol to the active session; however, the gel pad used during the sham session blocks the ultrasound such that none actually reaches the head. |
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| Primary | Motor Assessment 2: Finger Tapping (Score) | This task, which is item 3.4 on the Unified Parkinson's Disease Rating Scale (UPDRS), asks participants to tap their index finger on their thumb ten times as big and as fast as possible. Participants scores on item 3.4 with standard UPDRS scoring criteria (on a scale of 0 to 4, where a higher score indicates more severe Parkinson's symptoms i.e. worse performance) will be assessed pre and post-LIFUP. The scores reported below are for the hand on the side with worse symptoms (i.e. the side that LIFUP is intended to primarily affect). | One participant was not included in motor symptom analyses due to extreme motor symptom fluctuations at baseline confounding measurement of LIFUP-related changes | Posted | Mean | Standard Deviation | score on a scale | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
|
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| Primary | Motor Assessment 2: Finger Tapping (Speed) | This task, which is item 3.4 on the Unified Parkinson's Disease Rating Scale (UPDRS), asks participants to tap their index finger on their thumb ten times as big and as fast as possible. The speed of taps will be assessed pre and post-LIFUP. Speed is calculated as [number of taps per second] times [average tap amplitude], where tap amplitude is measured on a scale of 0.0-1.0 representing the percentage of finger extension between taps, where e.g. extension to a 90 degree angle between thumb and index finger = 1.0, extension to 45 degree angle = 0.5, etc. Higher speed indicates better performance. The speed values reported below are for the hand on the side with worse symptoms (i.e. the side that LIFUP is intended to primarily affect). | Posted | Mean | Standard Deviation | tap amplitude per second | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
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| Primary | Motor Assessment 2: 9-Hole Pegboard Dexterity Test | The participant will place and remove nine plastic pegs into a plastic pegboard. Scores are recorded as time in seconds that it takes the participant to complete the task with each hand. Analysis will compare pre- and post-treatment scores to quantify motor performance improvements. | Posted | Mean | Standard Deviation | Seconds | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
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| Secondary | Difference in BOLD fMRI Signal Between on vs. Off Blocks | BOLD data will be collected in real-time during the ultrasound sonication, which occurs in interleaved 30 second "on" and "off" blocks. Analyses will assess the statistical relationship between BOLD signal in the brain and the time series (on vs off) of the ultrasound sonication. Tabular data reported here represents the difference in BOLD activation between on and off conditions in the internal globus pallidus on the targeted side of the brain, calculated as the mean BOLD activation while LIFUP is on minus mean activation when it is off. | Three participants were excluded from this analysis due to excessive motion or preprocessing failure. | Posted | Mean | Standard Deviation | BOLD signal change | During LIFUP (or sham) sonication on Day 1 and Day 15 |
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| Secondary | Perfusion Changes in Internal Globus Pallidus, External Globus Pallidus, and Putamen | Arterial spin labeling data will be collected before and after sonication. Analyses will assess the statistical relationship between perfusion in the targeted internal globus pallidus, external globus pallidus, and putamen pre- and post-sonication in a within-subject repeated measures design. | Data from the active session from 11 participants and from the sham session for 5 participants were excluded due to incomplete data or image reconstruction or preprocessing failures. | Posted | Mean | Standard Deviation | percentage change | Pre-LIFUP and Post-LIFUP at Day 1 and Day 15 |
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| 0 |
| 30 |
| 0 |
| 30 |
| 5 |
| 30 |
| EG001 | Sham LIFUP Session | LIFUP will be administered with an identical protocol to the active session; however, the gel pad used during the sham session blocks the ultrasound such that none actually reaches the head. | 0 | 31 | 0 | 31 | 6 | 31 |
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| Fatigue or Sleep Disruption | General disorders | Systematic Assessment | Self-reported fatigue or other alterations to sleep patterns (insomnia, excessive sleep) |
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| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| Pre-LIFUP (Hand on side with less severe symptoms) |
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| Post-LIFUP (Hand on side with less severe symptoms) |
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| Putamen - Percent Change Perfusion |
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