Low Intensity Focused Ultrasound for Chronic Pain: High Resolution Targeting of the Human Insula (LIFU_Pain)

In this study, the research team will use low-intensity focused ultrasound (LIFU) to temporarily change brain activity in a brain region that is known to be involved in chronic pain. Through this, the research team hopes to learn about how the brain area works in response to pain. There are main questions this study aims to answer:

• The effect of LIFU to inhibit the posterior region of the insula (PI) compared to sham stimulation in individuals with chronic back pain (CBP) and widespread pain symptoms.
• The effect of LIFU to PI compared to sham stimulation to reduce pain intensity and magnitude of the Neurologic Pain Signature (NPS) in response to evoked thermal pain.
• The effect of LIFU to PI compared to sham stimulation to reduce pain intensity and magnitude of Tonic Pain Signature in response to tonic pain.

Study Overview

• Status: Recruiting
• Conditions: Chronic Back Pain; Chronic Pain (back / Neck)
• Intervention / Treatment: Device: low intensity focused ultrasound (LIFU)

Detailed Description

Chronic pain is a major public health problem. An estimated 100 million Americans have experienced chronic pain producing significant economic and social burden. The estimated annual cost of chronic pain is as high as $635 billion. Pharmacological treatments frequently require the use of opioids resulting in a major epidemic of abuse in the United States. New, non-addicting treatments for pain are critically needed. Neuromodulation with low-intensity focused ultrasound (LIFU) could represent a non-pharmacological treatment for chronic pain. The millimeter spatial specificity of LIFU makes it a powerful alternative to both invasive neurosurgical procedures and other noninvasive brain stimulation techniques. One promising target to treat chronic pain is the insular cortex. The insula as a key brain area involved in both sensory and affective components of chronic pain, including central sensitization processes which occur with pain chronicity. The insula is inaccessible using conventional noninvasive neuromodulatory techniques like transcranial magnetic stimulation. In contrast, LIFU can be focused deeply and provides the spatial resolution to resolve individual sub-regions of the insula. This is relevant to pain as the posterior subregion of the insula (PI) receives nociceptive input from spinothalamic tracts, relays it to the anterior insula which integrates expectation, awareness, and emotion to form the overall experience of pain. Therefore, using LIFU can address a gap in knowledge regarding the causal role of insular subregions in modulating pain response and CS processes. The preliminary data indicate that LIFU to PI reduces laboratory measures of central sensitization and evoked pain in healthy controls but there was no such effect of LIFU to anterior insula. Building on these results, the overall objective of this proposal is to examine the effect of LIFU to PI on the central sensitization processes that are a key feature of chronic pain syndromes and on neural response to evoked and tonic pain/pain intensity. The investigators will employ well validated laboratory measures of central sensitization and multivariate measures of neural response to evoked (Neurologic Pain Signature, NPS) and tonic (Tonic Pain Signature) pain. The chronic pain condition that the investigators will focus on in this study will be chronic back pain (CBP) with widespread pain widespread pain as the back is the most common site of chronic pain, is significantly more likely to be severe in the veteran population, and it commonly occurs with features of central sensitization. Eligible participants will have CBP with symptoms of widespread pain.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mary R Lee, MD; Phone Number: 58128 202-745-8000; Email: mary.lee3@va.gov
• Study Contact Backup: Name: Evan Evan Lindeman, MS; Email: evan.lindeman@va.gov

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Recruiting
      • Washington DC Veterans Affairs Medical Center
      • Contact: Mary R Lee, MD; Phone Number: 58128 202-745-8000; Email: mary.lee3@va.gov
      • Contact: Mary R Lee, MD
      • Contact: Evan Lindeman, MS; Email: evan.lindeman@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Veterans aged 21 to 75 with Chronic Back Pain (CBP).
• CBP duration daily for last 3 months or half of days for last 6 months
• Endorse pain rating of 4/10 BPI-SF
• Evidence of widespread pain symptoms as determined by report of CBP and pain in a contralateral limb (pain in the upper, lower, left or right side of the body) in fewer than 11 sites. Upper body sites include hand, wrist, elbow or shoulder. Lower sites include hip, knee, ankle or foot.

Exclusion Criteria:

• Surgery recommended as primary treatment intervention for CBP
• Current diagnosis of fibromyalgia
• Current substance use disorder other than nicotine.
• Psychiatric disorder and not on a stable pharmacologic regimen for ≥ 4 weeks prior to screening
• Opiate use daily
• Currently pregnant or breast feeding.
• Unable to understand the consent form.
• History of head injury with loss of consciousness for more than 5 minutes, seizures, history of stroke, brain surgery, brain tumor, multiple sclerosis.
• History of metastatic cancer, rheumatoid arthritis, polymyalgia rheumatica, scleroderma, lupus, or polymyositis
• Unintended weight loss of 20 pounds or more in the last year
• Cauda equina syndrome
• Ferromagnetic implants or other contraindications for MRI
• Uncompensated congestive heart failure, unstable angina, poorly controlled arrhythmia, active systemic infection end stage renal disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: LIFU/Sham; double-blind, sham-controlled, crossover study in N=66 individuals with Chronic Back Pain	Device: low intensity focused ultrasound (LIFU); Low-intensity focused ultrasound (LIFU) provides an energy source with millimeter resolution that can be focused anywhere in the brain safely and effectively for non-invasive and transient neuromodulation. LIFU is an important advance and of great significance for brain-mapping efforts, diagnostics, and therapies in neuroscience and particularly promising for addiction therapy as it provides unprecedented non-surgical access to the brain regardless of depth. Much lower intensities of focused ultrasound (LIFU) are used so that tissue damage does not occur, but neural activity can be modulated. LIFU utilizes acoustic energy at much lower levels to affect tissue by mechanical effects.
Other: Sham/LIFU; double-blind, sham-controlled, crossover study in N=66 individuals with Chronic Back Pain	Device: low intensity focused ultrasound (LIFU); Low-intensity focused ultrasound (LIFU) provides an energy source with millimeter resolution that can be focused anywhere in the brain safely and effectively for non-invasive and transient neuromodulation. LIFU is an important advance and of great significance for brain-mapping efforts, diagnostics, and therapies in neuroscience and particularly promising for addiction therapy as it provides unprecedented non-surgical access to the brain regardless of depth. Much lower intensities of focused ultrasound (LIFU) are used so that tissue damage does not occur, but neural activity can be modulated. LIFU utilizes acoustic energy at much lower levels to affect tissue by mechanical effects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measures of Central Sensitization - Thermal Pain Threshold	For the first measure, the probe is placed on the skin on the ventral aspect of the forearm on the nondominant arm. The temperature is set at 32°C and the temperature is increased at a rate of 1°C/s to a maximum of 52°C. Participants will be asked to press a button when the heat reaches a painful level. The outcome is the temperature at this level. Heat PT are averaged over three trials each separated by 40 seconds. Thermal PT will be performed prior to and after LIFU. On each trial, the thermode is moved to a different site on the forearm to avoid sensitization and response suppression of cutaneous heat receptors.	immediately prior to 1 session LIFU and within 1 hour post LIFU; immediately prior to 1 session sham and with in 1 hour post shamdays
Measures of Central Sensitization - Temporal Summation of Pain	The second measure refers to the perception of increasing pain in response to repeated same noxious stimuli delivered at a frequency of > 0.33 Hz. Temporal summation of pain serves as a proxy measure of pain facilitation and CS. Individuals with enhanced temporal summation of pain have facilitated ascending nociceptive processing and reduced pain-modulatory capacities. Following the temporal summation of pain paradigm, three stimulus trains of trapezoid heat pulses of 1.5 s duration will be delivered to the dorsum of the dominant hand at an inter-pulse interval of 2.5 seconds at individual subject heat pain of 6/10 on numeric pain rating scale. A total of 5 stimuli will be delivered per train. Participants will be required to rate each stimulus (0-10). The Δ scores from 5th to 1st stimulus of each train will be averaged.	immediately prior to 1 session LIFU and within 1 hour post LIFU; immediately prior to 1 session sham and with in 1 hour post shamdays
Measures of Central Sensitization - Conditioned Modulation of Pain	A type of counter-irritation paradigm that can be used as a proxy measure for descending anti-nociceptive or pain modulation activity. CPM involves presentation of a conditioning pain stimulus to a remote area of the body while a nociceptive (test) stimulus (TS) is applied to the contralateral (heterotopic) area. We will employ conditioned modulation of pain according to using a sequential conditioning-test stimulus protocol as recommended by. The test stimulus consists of a two-minute thermal stimulus applied with the thermode at a rating of 5/10 on the numeric pain rating scale. Participants will rate their perceived pain (0-10, numeric pain rating scale) every 15 seconds. This will be performed pre/post the conditioning stimulus. The conditioning stimulus will be a cold pressor test.. The non-dominant arm will be immersed in a cold-water bath (12°C) for two minutes. This method recruits inhibitory conditioned modulation of pain because it is a strong nociceptive stimulation.	immediately prior to 1 session LIFU and within 1 hour post LIFU; immediately prior to 1 session sham and with in 1 hour post shamdays

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurologic Pain Signature	A secondary outcome is the pain intensity and magnitude of the NPS in response to evoked thermal pain using task-based functional magnetic resonance imaging.	immediately prior to 1 session LIFU and within 1 hour post LIFU; immediately prior to 1 session sham and with in 1 hour post shamdays
Tonic Pain Signature	A secondary outcome is the pain intensity and magnitude of Tonic Pain Signature in response to tonic pain using resting-state functional magnetic resonance imaging.	immediately prior to 1 session LIFU and within 1 hour post LIFU; immediately prior to 1 session sham and with in 1 hour post sham

Collaborators and Investigators

• Sponsor: Washington D.C. Veterans Affairs Medical Center
• Investigators: Principal Investigator: Mary R Lee, MD, Washington D.C. Veterans Affairs Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2025
• Primary Completion (Estimated): January 26, 2028
• Study Completion (Estimated): January 26, 2028

Study Registration Dates

• First Submitted: February 13, 2025
• First Submitted That Met QC Criteria: March 25, 2025
• First Posted (Actual): April 2, 2025

Study Record Updates

• Last Update Posted (Actual): April 2, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: chronic pain; functional magnetic resonance imaging; chronic back pain; low intensity focused ultrasound
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Back Pain; Chronic Pain
• Other Study ID Numbers: 1781312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: behavioral and imaging data
• IPD Sharing Time Frame: data will be available after analysis of primary and secondary outcomes are completed
• IPD Sharing Supporting Information Type: SAP; ANALYTIC_CODE

Drug and device information, study documents

• 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