Low Intensity Ultrasound Neuromodulation of Repetitive Negative Thinking In Depression

NCT05697172 | Completed DMC

• 1 other identifier: 2021-011
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators propose to use low-intensity transcranial focused ultrasound (LIFU), a novel neuromodulation method, to probe the causal involvement of individually defined components of an anteromedial brain circuit in the processing of self-referential thoughts, and the production of repetitive negative thinking (RNT), a prominent transdiagnostic manifestation with adverse clinical consequences. The investigators hypothesize that real vs. sham low-intensity sonication of individually-defined anteromedial structures connecting medial orbitofrontal and anterior cingulate cortices with ventral striatum and anterior thalamus will show reduced initiation or maintenance of RNT as measured by (1) Brief State Rumination Inventory (BSRI) scores and distress associated to repetitive negative thoughts, and (2) improvement of the affective valence associated to self-referential adjectives, and that these changes will be associated with decreased connectivity between structures mentioned above. The present early feasibility study is an initial step that aims to determine its feasibility and help with the planning of a larger study addressed at actual hypothesis testing.

Conditions

Major Depressive Disorder

Keywords

Repetitive Negative Thinking; Low-Intensity Focused Ultrasound; Major Depression

Outcome Measures

Primary Outcomes (1)

• Post-Sonication Change in the Intensity of Repetitive Negative Thinking

  Change of BSRI (Brief State Rumination Inventory) score; minimum value: 0, maximum value: 800; higher scores mean worse outcome.

  Pre- vs 10-minute post-sonication or sham intervention.

Secondary Outcomes (1)

• Suicide Safety Indicators

  Pre- vs 1-hour and 1-week post-sonication or sham intervention.

Study Arms (2)

Active Low Intensity Focused Ultrasound (LIFU)

EXPERIMENTAL

An 80-second train of 20-millisecond bursts of ultrasound (0.5 MHz), repeated every 200 milliseconds (400 bursts). Acoustic simulations will be performed with the k-Wave Matlab Toolbox to individually confirm the estimated total energy delivered during sonication and verify tissue temperature increases are \<1°C, decreasing actual Power/Channel values if necessary. We estimate a 75% tissue attenuation of energy when the ultrasound wave reaches its target, therefore we will set the free-field Intensity Spatial-Peak Pulse-Average (ISPPA) at 9.04 Watt /cm2 or 518 kPascal (to achieve 2.26 Watt/cm2 derated ISPPA).

Other: Low-intensity focused ultrasound

Sham LIFU

SHAM COMPARATOR

Identical parameters of sonication and positioning procedures as those in the Active LIFU arm will be employed, but a Sorbothane(R) film will be interposed between the transducer and the subject's scalp.

Other: Low-intensity focused ultrasound

Interventions

Low-intensity focused ultrasound OTHER

80-second stimulus with an estimated tissue ISSPA=2.26 W/cm2, with (sham) or without (verum) interposition of Sorbothane film

Active Low Intensity Focused Ultrasound (LIFU); Sham LIFU

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Prior participation in the CoBRE study (WIRB Protocol #20182352) and selected as a component of the propensity-matched sample of patients with major depression and varying intensities of RNT (in the form of Ruminative Response Scale (RRS) score; n=20), or healthy individuals with no psychiatric diagnosis (n=10), OR In the unexpected event that not enough participants can be recruited who meet criterion 1 (only 1 out of 6 studied patients would be incorporated into this study), participants will be newly recruited from newly recruited patients from the community or from the Mood and Anxiety Disorders inpatient unit at Laureate Psychiatric Hospital and Clinic.
• A Patient Health Questionnaire (PHQ-9) score ≥ 10 at enrollment.
• Provision of signed and dated informed consent form.
• Subject provides verifiable contact information (name, telephone number(s), email and mailing address) for at least 2 persons who agree to be contacted by study personnel as deemed necessary.
• Subject is followed by a licensed physician or a licensed mental health care provider (i.e., psychologist, LCSW) throughout study participation outside of LIBR.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, aged 18 to 65 years.
• In good current general health as evidenced by medical history.
• Ability to comply with the study chronogram.
• For females of reproductive potential: negative urine pregnancy screening test.

You may not qualify if:

• Current use (within the last 30 days) of drugs of abuse or moderate / severe alcohol use disorder.
• Lifetime diagnosis of schizophrenia spectrum disorder, other nonaffective psychotic disorders, or bipolar disorders.
• Presence of cardiac pacemaker or any other MRI contraindication.
• Pregnancy or lactation.
• Febrile illness within the last two weeks.
• Treatment with an investigational drug or participation in any other interventional research protocol in the last 2 weeks.
• The participant is unable to understand the goal of the study, instructions, or the risks associated with the study as judged by a clinically trained assessment team member.
• Clinical and/or imaging evidence of vascular, traumatic, or neurodegenerative disorders of the central nervous system (CNS), or other neurological disorders potentially compromising patient's participation in the study, or study results. This includes, but it is not limited to, any minor or major neurocognitive disorder including those caused by traumatic brain injury, Parkinson's disease, significant small-vessel disease, multiple sclerosis, Huntington's disease, early-onset Alzheimer's disease, chronic infections of the CNS or the meninges, previous chronic use of alcohol or CVA sequelae, or a Montreal Cognitive Assessment (MoCA) score \<25 due to any cause. The PI can decide if a potential participant needs to be excluded due to some other cause of structural or functional compromise of the CNS (e.g., epilepsy).
• Active suicidal ideation (as measured by Suicide-Risk-Assessment-C-SSRS "Yes" answers to items 3, 4 or 5 of Suicidal Ideation-Past 1 month section, or any "Yes" answer to any of the items of Suicidal Behavior-Past 3 months section), or any suicide attempt in the last year.

Sponsors & Collaborators

• Laureate Institute for Brain Research, Inc.: lead

Study Sites (1)

Laureate Institute for Brain Research

Tulsa, Oklahoma, 74136, United States

Location

Related Publications (1)

• Tsuchiyagaito A, Kuplicki R, Misaki M, Edwards L, Camprodon JA, Fitzgerald K, Khalsa SS, Philip NS, Paulus MP, Guinjoan SM. Reversible modulation of a deep white matter surgical target for depression with low-intensity focused ultrasound. Neuropsychopharmacology. 2026 Feb;51(3):612-621. doi: 10.1038/s41386-025-02252-7. Epub 2025 Sep 25.

  PMID: 40999237 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: A sound proof material will be employed to deliver sham stimulation. The operator of the device will be unblinded to the type of intervention (verum vs sham). Participant, assessment team including raters, and staff responsible for evaluation of psychiatric and neurological status will be blind to the intervention.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: An exploratory hypothesis is that stimulation of anteromedial structures of the telencephalic cortex of the right hemisphere and their connections with subcortical structures will lead to detectable attenuation of RNT in high RNT depressed individuals. In this study, the investigators will use a double-blind, randomized cross-over design employing either tfUS or sham stimulation. The proposed design parsimoniously follows the approved pilot study supported by the Center of Biomedical Research Excellence grant NeuroMAP (P20GM121312), in which the investigators will characterize neural circuits associated to RNT.

Study Record Dates

• First Submitted: November 11, 2022
• First Posted: January 25, 2023
• Study Start: December 15, 2022
• Primary Completion: February 6, 2024
• Study Completion: February 6, 2024
• Last Updated: August 5, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)