Low Intensity Ultrasound Neuromodulation of Repetitive Negative Thinking In Depression

August 2, 2024 updated by: Laureate Institute for Brain Research, Inc.

Neuromodulation of Circuits Underlying Repetitive Negative and Self-Referential Thinking in Depression: An Early Feasibility Study Employing Transcranial Focused Ultrasound

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Depression represents a remarkable public health burden, accounting for a large amount of disability and societal costs, comparable to prevalent diseases in other areas of medicine. This is partly due to unsatisfactory outcomes of well-established therapies, including psychotropic drugs and different types of psychotherapy. As a response to this problem, therapeutics in psychiatry is moving from drug manipulation of neurotransmitter systems to modulation of brain circuits selectively involved in specific symptoms of depression. These efforts have been partially hampered, however, by heterogeneity of clinical manifestations in these disorders, such that different symptoms are hypothesized to be maintained by specific circuit-level dysfunctions, as well as by significant interindividual variation in those brain circuits, which calls for personalized approaches to achieve their successful modulation. Thus far, the efforts to accomplish individualized and precise modulation of aberrant circuits responsible for the expression of depression and anxiety symptoms have encountered three important, mutually related problems. First, widely available noninvasive neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS) have poor spatial resolution and only reach superficial areas of the brain, which impedes the precise modulation of circuits that involve deep, minute subcortical gray matter structures and/or white matter connecting tracts. Second, surgical deep-brain stimulation procedures are more accurate but are too costly and risky to be implemented in any moderately sized proof-of-concept study at present. Third, it is unlikely that modification of the activity of a discrete brain circuit will target the entire complex behavioral macro of major depression. The investigators therefore chose to target a single measurable and replicable construct of depression, repetitive negative thinking (RNT). RNT is a transdiagnostic clinical manifestation that cuts across a variety of internalizing psychiatric disorders, but in the case of depression, it is associated with persistent symptoms, treatment resistance, proneness to relapse after treatment, and more suicidal ideation, behavior, and completed suicides. With the help of an emerging technology device recently acquired by LIBR, which can produce focused, reversible and noninvasive neuromodulation in deep brain structures (low-intensity transcranial focused ultrasound, tfUS), the investigators will probe the causal role of individually-identified circuits in the modulation of (a) the generation and maintenance of repetitive negative thinking (RNT), and (b) affective processing of self-referential adjectives. Specifically, the investigators will put to test the hypotheses that RNT and the affective load of self-referential adjectives can be improved by modulating components of an anteromedial brain circuit, identified on an individual basis as associated with high levels of RNT. Therefore, this project has two distinct phases. First, the investigators will use advanced structural-functional connectivity analysis techniques to define anatomical tracts that support functional connectivity alterations associated with high RNT. The investigators will refine and adjust results of whole-brain analyses, by focusing also on overlapping anatomical components of tracts pertaining to three well-established, historical psychosurgical targets of antidepressant and obsessional thinking treatment. Second, the investigators will employ the resulting regions of interest to inform the choice of the target(s) for tfUS neuromodulation, probing its effects on 1) neural processing of self-referential affective adjectives, 2) functional connectivity between regions known to have an anatomical connection in the individual participant, and 3) measures of RNT and clinical depression, including the degree of distress associated to the thought/s subjected to RNT. The investigators are in an ideal position to accomplish these objectives, given their experience with clinical management of these disorders, with the use of neuromodulation techniques, and expertise in the use of state-of-the-art structural and functional neuroimaging techniques, psychophysiological tools, and computational psychiatry methods.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Oklahoma
      • Tulsa, Oklahoma, United States, 74136
        • Laureate Institute for Brain Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  1. 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.
  2. A Patient Health Questionnaire (PHQ-9) score ≥ 10 at enrollment.
  3. Provision of signed and dated informed consent form.
  4. 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.
  5. Subject is followed by a licensed physician or a licensed mental health care provider (i.e., psychologist, LCSW) throughout study participation outside of LIBR.
  6. Stated willingness to comply with all study procedures and availability for the duration of the study.
  7. Male or female, aged 18 to 65 years.
  8. In good current general health as evidenced by medical history.
  9. Ability to comply with the study chronogram.
  10. For females of reproductive potential: negative urine pregnancy screening test.

Exclusion Criteria:

  1. Current use (within the last 30 days) of drugs of abuse or moderate / severe alcohol use disorder.
  2. Lifetime diagnosis of schizophrenia spectrum disorder, other nonaffective psychotic disorders, or bipolar disorders.
  3. Presence of cardiac pacemaker or any other MRI contraindication.
  4. Pregnancy or lactation.
  5. Febrile illness within the last two weeks.
  6. Treatment with an investigational drug or participation in any other interventional research protocol in the last 2 weeks.
  7. 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.
  8. 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).
  9. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Active Low Intensity Focused Ultrasound (LIFU)
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
80-second stimulus with an estimated tissue ISSPA=2.26 W/cm2, with (sham) or without (verum) interposition of Sorbothane film
Sham Comparator: Sham LIFU
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
80-second stimulus with an estimated tissue ISSPA=2.26 W/cm2, with (sham) or without (verum) interposition of Sorbothane film

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Post-Sonication Change in the Intensity of Repetitive Negative Thinking
Time Frame: Pre- vs 10-minute post-sonication or sham intervention.
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Suicide Safety Indicators
Time Frame: Pre- vs 1-hour and 1-week post-sonication or sham intervention.
Change in Columbia-Suicide Severity Rating Scale (C-SSRS) score, minimum value: 0; maximum value: 25; higher scores mean worse outcome.
Pre- vs 1-hour and 1-week post-sonication or sham intervention.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Laureate Institute for Brain Research, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 15, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 6, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 6, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 11, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 16, 2023

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 25, 2023

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 5, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 2, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2024

More Information

Terms related to this study

Keywords

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Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2021-011

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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