Low Intensity Focused Ultrasound Pulses (LIFUP) to Modulate Pain

• Sponsor: Medical University of South Carolina (Other)
• Overall Status: Completed
• CT.gov ID: NCT04339972
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arms: 2
• Actual Duration (Months): 28.9
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The anterior nuclei of the thalamus in addition to periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are integral regions of a supraspinal opioidergic structure that regulate pain perception. With the capability to influence deep neurological tissues, low intensity frequency ultrasound pulsation (LIFUP) can likely modulate this circuit and induce analgesia. LIFUP deep brain modulation is achieved by induction of focused mechanical waveforms that traverse the cranium and underlying brain tissue. The low frequency of the ultrasonic wave consequently alters neuronal transmission and causes action potential variations through mechanical means, rather than thermal.

The purpose of this study is to examine whether stimulation of the anterior nuclei of the thalamus via LIFUP induces analgesia. We hypothesize that suppression of the anterior nuclei of the thalamus will induce a temporary increase in pain tolerance. Moreover, the behavioral changes in pain will correlate with specific regional BOLD changes during pain.

Condition or Disease	Intervention/Treatment	Phase
Healthy Adults	Device: LIFUP; Device: Sham LIFUP	N/A

Detailed Description

LIFUP uses a single large concave, or multiple ultrasound transducers in a cap placed on the scalp to produce high frequency (100Hz) sonications for 30 seconds at a time for 10 trains of pulses. Unlike traditional diagnostic ultrasound, which constantly transmits ultrasound and 'listens' to the echo to form an image, LIFUP delivers the ultrasound in packets or pulses. For reasons that are not clear, pulsed ultrasound causes neurons to depolarize and fire. Bones typically block ultrasound waves. Cleverly, however, one can deliver the ultrasound from multiple sources and use the skull as a lens, to actually shape and focus the convergent beam deeper in the brain.

The clinical use of LIFUP thus uses MRI scans taken before stimulation to position and calculate how multiple ultrasonic pulsations will converge at a location in the brain (taking into account the bone dispersion of the beam from the skull). Since a small transducer like in diagnostic ultrasound cannot individually cause neuronal discharge, with LIFUP neuronal firing can be focused both deep (2-12cm under the cap; for comparison, traditional TMS can stimulate 1-3.4cm2 deep(9, 10)) and focally (as small as 0.5mm in diameter, and up to 1000mm; the facility of a standard, commercially-available 70mm figure-of-8 TMS coil is roughly 50mm2; (9, 10)). Interestingly, the pulse width of the carrying frequency of LIFUP (0.5ms) is strikingly similar to that used in all other pulsed neuromodulation therapies (DBS: 0.6ms, ECT: 0.5ms; TMS: 0.2ms; VNS: 0.5ms), suggesting that this timeframe is mechanistically meaningful. This is a good example of the common background science of brain stimulation that transcends the individual methods.

Researchers have examined the effects of LIFUP in preclinical and clinical settings, confirming its ability to safely stimulate neural tissue(11-14), proposing cellular mechanisms for its efficacy(13-19), and now using LIFUP in human patients(20). Monti et al. (2016) described a case study in which they used LIFUP to stimulate a comatose patient's thalamus.(20). Two pre-LIFUP assessments rated the patient as being in minimally conscious state (MCS). After sonication, the patient recovered motor and oromotor functions the next day, advancing to full language comprehension and communication by nodding and shaking his head. Five days post-LIFUP, the patient attempted to walk. While this study was neither blinded nor sham-controlled, the first application of therapeutic LIFUP in a human patient was encouraging and we expect more therapeutic applications of LIFUP and potential clinical trials in the future. If LIFUP continues to show clinical potential, it has the potential to supplant the role of DBS without the need for surgery. The key barrier to LIFUP replacing DBS for clinical applications is that by and large, DBS is used in a manner where the device is inserted and turned constantly on without attempting to fundamentally change circuit dynamics or behavior so that you could remove the device. Obviously, patients cannot permanently wear a LIFUP helmet. However, to the degree that we learn how to stimulate in ways that permanently change circuit behavior (LTD or LTP) without ablation, we may be able to substitute several sessions of LIFUP that can train and rewire the brain instead of permanently implanting hardware. LIFUP can certainly stimulate deep and focal and noninvasively and thus may be a key next step in the field of brain stimulation.

Information on the intervention to be studied. We will be using the Brainsonix Low intensity focused ultrasound pulsation device. (BX Pulsar 1001). Please see the manufacturers description (Technical Summary) along with appendixes about the actual safety of the device itself.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Low Intensity Focused Ultrasound Pulses (LIFUP) to Modulate Pain
• Actual Study Start Date: Feb 1, 2019
• Actual Primary Completion Date: Jul 1, 2020
• Actual Study Completion Date: Jul 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active LIFUP then Sham LIFUP Real LIFUP is delivered to the participant for visit 1, followed by sham lifup visit 2	Device: LIFUP; Low Intensity Focused Ultrasound Pulsation (LIFUP) is an interesting new form of brain stimulation that may be possible to stimulate non-invasively, safely, deep in the brain with focal precision.
Sham Comparator: Sham LIFUP then Active LIFUP Sham LIFUP is delivered to the participant for visit 1, followed by real lifup visit 2	Device: Sham LIFUP; The same as LIFUP but the device is not turned on and the subject does not receive any ultrasound.

Outcome Measures

Primary Outcome Measures

1. Quantitative Sensory Threshold Temperature Levels (Degrees Celsius) [Change from Baseline 45 minutes after LIFUP in the scanner]

   Quantitative Sensory Testing (QST) is a valuable method for diagnosing peripheral nervous system disorders, including pain. This outcome quantifies the level of thermal stimulus temperature (degrees celsius) required for a participant to feel pain on their wrist. The temperatures will be recorded before and after LIFUP.

2. Number of Participants With Significant Functional MRI Blood Oxygen Level Dependent (BOLD) Signal Changes [Changes within 3 seconds after receiving LIFUP]

   Blood oxygenation level dependent (BOLD) imaging is the standard technique used to generate images in functional MRI (fMRI) studies, and relies on regional differences in cerebral blood flow to delineate regional activity. We will measure the brain's BOLD signal as a response to thermal stimulus within the MRI scanner and determine whether a significant (p ≤ 0.005 uncorrected) increase or decrease in BOLD signal intensity is indicated as a result of either Active or Sham LIFUP.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• 18-45 years of age

• Healthy volunteer

Exclusion Criteria:

• seizure history (individual or family)

• history of depression

• hospitalizations or surgeries in the previous 6 months

• currently experiencing pain

• history of chronic pain

• metal implants or objects (e.g. pacemakers, metal plates, wires)

• pregnant

• alcohol dependence

• illicit drug use in the previous 6 months

• known allergy to capsaicin

• history of brain surgery or brain lesions

• history of loss of consciousness (greater than 15 min)

• on stimulants or medications that lower seizure threshold.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of South Carolina	Charleston	South Carolina	United States	29425

Sponsors and Collaborators

• Medical University of South Carolina

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 12, 2019

More Information

Publications

None provided.

• Responsible Party: Medical University of South Carolina
• ClinicalTrials.gov Identifier: NCT04339972
• Other Study ID Numbers: Pro00082376
• First Posted: Apr 9, 2020
• Last Update Posted: Aug 19, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Study Results

Participant Flow

Arm/Group Title	Active LIFUP Followed by Sham LIFUP	Sham LIFUP Followed by Active LIFUP
Arm/Group Description	Real LIFUP is delivered to the participant during this condition. LIFUP: Low Intensity Focused Ultrasound Pulsation (LIFUP) is an interesting new form of brain stimulation that may be possible to stimulate non-invasively, safely, deep in the brain with focal precision.	Sham LIFUP (device turned on but no sonication delivered) during this condition Sham LIFUP: The same as LIFUP but the device is not turned on and the subject does not receive any ultrasound.
Period Title: Overall Study
STARTED	15	14
COMPLETED	10	9
NOT COMPLETED	5	5

Baseline Characteristics

Arm/Group Title	Active LIFUP Followed by Sham LIFUP	Sham LIFUP Followed by Active LIFUP	Total
Arm/Group Description	Real LIFUP is delivered to the participant during this condition. LIFUP: Low Intensity Focused Ultrasound Pulsation (LIFUP) is an interesting new form of brain stimulation that may be possible to stimulate non-invasively, safely, deep in the brain with focal precision.	Sham LIFUP (device turned on but no sonication delivered) during this condition Sham LIFUP: The same as LIFUP but the device is not turned on and the subject does not receive any ultrasound.	Total of all reporting groups
Overall Participants	10	9	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	9 100%	19 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.5 (4.6)	24.5 (4.6)	24.5 (4.6)
Sex: Female, Male (Count of Participants)
Female	6 60%	5 55.6%	11 57.9%
Male	4 40%	4 44.4%	8 42.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	10 100%	9 100%	19 100%
Region of Enrollment (Count of Participants)
United States	10 100%	9 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Quantitative Sensory Threshold Temperature Levels (Degrees Celsius)
Description	Quantitative Sensory Testing (QST) is a valuable method for diagnosing peripheral nervous system disorders, including pain. This outcome quantifies the level of thermal stimulus temperature (degrees celsius) required for a participant to feel pain on their wrist. The temperatures will be recorded before and after LIFUP.
Time Frame	Change from Baseline 45 minutes after LIFUP in the scanner

Outcome Measure Data

Analysis Population Description

This was a crossover design so everyone in the study recieved both active and sham lifup, randomized order. Overall analysis was conducted in a repeated measure, within subject design for all 19 participants.

Arm/Group Title	Active LIFUP	Sham LIFUP
Arm/Group Description	Real LIFUP is delivered to the participant for either visit 1 or visit 2.	Sham LIFUP is delivered to the participant for visit 1 or visit 2.
Measure Participants	19	19
Mean (Standard Error) [Degrees Celsius]	.51 (.3)	1.08 (.28)

2. Primary Outcome

Title	Number of Participants With Significant Functional MRI Blood Oxygen Level Dependent (BOLD) Signal Changes
Description	Blood oxygenation level dependent (BOLD) imaging is the standard technique used to generate images in functional MRI (fMRI) studies, and relies on regional differences in cerebral blood flow to delineate regional activity. We will measure the brain's BOLD signal as a response to thermal stimulus within the MRI scanner and determine whether a significant (p ≤ 0.005 uncorrected) increase or decrease in BOLD signal intensity is indicated as a result of either Active or Sham LIFUP.
Time Frame	Changes within 3 seconds after receiving LIFUP

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active LIFUP	Sham LIFUP
Arm/Group Description	Real LIFUP is delivered to the participant for either visit 1 or visit 2.	Sham LIFUP is delivered to the participant for visit 1 or visit 2.
Measure Participants	19	19
Number [Participants w/ significant BOLD changes]	0 0%	0 0%

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	LIFUP is a safe form of brain stimulation with no risk of adverse events when administered at this intensity
Arm/Group Title	Active LIFUP		Sham LIFUP
Arm/Group Description	Real LIFUP is delivered to the participant for visit 1 or visit 2.		Sham LIFUP is delivered to the participant for visit 1 or visit 2.
All Cause Mortality
	Active LIFUP		Sham LIFUP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)
Serious Adverse Events
	Active LIFUP		Sham LIFUP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Active LIFUP		Sham LIFUP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.