Low Intensity Focused Ultrasound: a New Paradigm for Depression and Anxiety

NCT05147142 | Active Not Recruiting DMC FDA Device

• 1 other identifier: IRB-2020-053
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Objective: Preliminary studies show that low intensity focused ultrasound (LIFU), a new type of non invasive brain stimulation, may be able to reach deep structures of the brain involved with depression and anxiety, that remain inaccessible using current forms of non-invasive brain stimulation with precision. In this study, the investigators will test if this technique can be used to change brain activity in areas that are connected to depression and anxiety symptoms. The primary objectives of this study are to test the safety and tolerability of LIFU, evaluate the feasibility of using LIFU to reduce brain activity, and evaluate the feasibility of simultaneous fMRI-LIFU. If the results of this study are positive, what the investigators learn will serve as a strong foundation for the future development of innovative treatments for a variety of psychiatric disorders. Research Procedures: 25 veterans will be recruited. Visits will take place at the VA Providence Healthcare System. During some visits, healthy and patient participants may undergo clinical and research neuroimaging, neuropsychological testing, complete questionnaires, and participate in clinical/neurological assessments. Healthy veterans will not receive LIFU and will only attend 2 study visits. Patients are expected to attend up to 8 visits over 6 weeks. However, some may require up to 6 extended follow-ups after visits 5 or 8, in which case they would attend a total of 11 or 14 visits over 6 months. Two patient visits will include the LIFU application, following FDA safety guidelines. Patients will be assigned either to an experiment in which LIFU stimulation will be delivered immediately prior to a task or to an experiment in which stimulation will be delivered during the task. Within each experiment, patients will be assigned to first receive either LIFU stimulation to the study target or anatomical control. Study staff, but not participants will know which location is being targeted in case safety concerns arise. Safety assessments will be conducted at follow-up visits. A clinician will be available during LIFU administration /follow-up visits. Assuming no injury or other concerns are present, patients will then repeat this process again, receiving stimulation targeting other brain area not previously selected.

Conditions

Depression

Keywords

Functional Neuroimaging; Acoustic Stimulation; Focused Ultrasound

Outcome Measures

Primary Outcomes (6)

• Incidence of LIFU-related adverse events as assessed by clinical MRI

  MRI safety and monitoring will be determined through the review of clinical MRIs. The clinical MRI will be used to detect possible LIFU-induced injury including edema or other injury and microvascular damage. While the investigators believe hyperacute injury to be unlikely, scans at 24 hours and 1-week will be used to monitor for later evolving injury. If injury is detected on any participant at any stage of the study, the investigators will halt all study procedures.

  up to 6 months post LIFU

• Incidence of LIFU-related adverse events as assessed by neurological examinations

  Neurological exams will be used to detect any possible LIFU-induced neurological changes.

  up to 6 months post LIFU

• Incidence of LIFU-related adverse events as assessed by neuropsychological testing

  The investigators will evaluate safety using standardized neuropsychological tests at baseline, 24 hours, and 1-week post LIFU. The Repeatable Battery for the Assessment of Neurocognitive Status (RBANS) will be used to measure attention, language, visuospatial/construction, immediate, and delayed memory and to measure any possible LIFU-induced changes across these domains.

  up to 6 months post LIFU

• Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain

  Perfusion ASL fMRI data will be collected before and after sonication. Analyses will assess the statistical relationship between ASL signal throughout the brain pre and post sonication.

  change from baseline to following sonication

• BOLD fMRI Signal

  BOLD data will be collected before, during, and following LIFU sonication. Analyses will assess any changes in BOLD signal in the brain following sonication.

  change from baseline to following sonication

• Resting state functional connectivity

  Resting state data will be collecting before, during, and following LIFU sonication. Analyses will assess any functional connectivity changes in the brain following sonication.

  change from baseline to following sonication

Study Arms (2)

Target Site Low Intensity Focused Ultrasound

EXPERIMENTAL

Low Intensity focused ultrasound of the target region. These are at a fundamental frequency = 650kHz, PRF = 10Hz, pulse width = 5ms, duty cycle = 5%; ISPTA.3 of 720 mW/cm2. As in prior studies, each sonication includes 10 pulsations, each lasting 30s, followed by 30s pause intervals; two 10-minute administrations provided per LIFU session.

Device: Low Intensity Focused Ultrasound

Control Site Low Intensity Focused Ultrasound

ACTIVE COMPARATOR

Low Intensity focused ultrasound of the control region. These are at a fundamental frequency = 650kHz, PRF = 10Hz, pulse width = 5ms, duty cycle = 5%; ISPTA.3 of 720 mW/cm2. As in prior studies, each sonication includes 10 pulsations, each lasting 30s, followed by 30s pause intervals; two 10-minute administrations provided per LIFU session.

Device: Low Intensity Focused Ultrasound

Interventions

Low Intensity Focused Ultrasound DEVICE

Brainsonix BX Pulsar 1002

Also known as: LIFU

Control Site Low Intensity Focused Ultrasound; Target Site Low Intensity Focused Ultrasound

Eligibility Criteria

• Age: 22 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must meet DSM-5 criteria for major depressive disorder with and without anxiety symptoms
• Patients must also be symptomatic (i.e. symptom severity above clinical thresholds using standard rating scales) and, if relevant, stable treatment(s) for \>6 weeks.

You may not qualify if:

• history of seizure disorder or serious neurologic illness including dementia
• structural or neurologic abnormalities present or in close proximity to sonication site for patients (e.g., clinically significant calcification as might be observed in Fahr disease)
• history of brain surgery, iv) pacemaker or implanted central nervous system device
• greater than mild traumatic brain injury, or any head injury within sixty days of participation
• greater than moderate alcohol or substance use disorders (last six months; excluding nicotine/caffeine)
• active use or withdrawal from alcohol or substances (assessed via breathalyzer/urine testing as indicated)
• metal in the head
• impediment to vision, hearing and/or hand use likely to interfere with assessments
• pregnant or lactating (assessed via pregnancy test)
• unable to follow protocols
• acute suicidality, defined as "Yes" on item 4 of the Columbia Suicide Severity Rating Scale (C-SSRS), (i.e., active suicidal ideation with some intent to act on thoughts), or any endorsement of item 5 (active ideation with specific plan and intent) or any actual, interrupted, aborted attempt or preparatory behavior within the past month.
• symptom threshold considered in the "very severe" range using standard rating scales will be excluded.

Sponsors & Collaborators

• Ocean State Research Institute, Inc.: lead

Study Sites (1)

VA Providence Healthcare System

Providence, Rhode Island, 02908, United States

Location

Related Publications (6)

• Korb AS, Shellock FG, Cohen MS, Bystritsky A. Low-intensity focused ultrasound pulsation device used during magnetic resonance imaging: evaluation of magnetic resonance imaging-related heating at 3 Tesla/128 MHz. Neuromodulation. 2014 Apr;17(3):236-41; discussion 241. doi: 10.1111/ner.12075. Epub 2013 May 10.

  PMID: 23663228 BACKGROUND

• Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM. Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. Brain Stimul. 2016 Nov-Dec;9(6):940-941. doi: 10.1016/j.brs.2016.07.008. Epub 2016 Jul 22. No abstract available.

  PMID: 27567470 BACKGROUND

• Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A. Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies. Brain Stimul. 2019 Nov-Dec;12(6):1367-1380. doi: 10.1016/j.brs.2019.07.024. Epub 2019 Jul 31.

  PMID: 31401074 BACKGROUND

• Badran BW, Caulfield KA, Stomberg-Firestein S, Summers PM, Dowdle LT, Savoca M, Li X, Austelle CW, Short EB, Borckardt JJ, Spivak N, Bystritsky A, George MS. Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: A double-blind, sham-controlled study. Brain Stimul. 2020 Nov-Dec;13(6):1805-1812. doi: 10.1016/j.brs.2020.10.007. Epub 2020 Oct 24.

  PMID: 33127579 BACKGROUND

• Philip NS, Arulpragasam AR. Reaching for the unreachable: low intensity focused ultrasound for non-invasive deep brain stimulation. Neuropsychopharmacology. 2023 Jan;48(1):251-252. doi: 10.1038/s41386-022-01386-2. No abstract available.

  PMID: 35869281 BACKGROUND

• Arulpragasam AR, van 't Wout-Frank M, Barredo J, Faucher CR, Greenberg BD, Philip NS. Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. Front Psychiatry. 2022 Feb 24;13:825802. doi: 10.3389/fpsyt.2022.825802. eCollection 2022.

  PMID: 35280168 BACKGROUND

MeSH Terms

Conditions

Depression

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Study Officials

• Noah S Philip, MD

  VA Providence Healthcare System

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Single blind administration
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2021
• First Posted: December 7, 2021
• Study Start: September 28, 2021
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: March 11, 2026

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)