Ultrasound Neuromodulation of Circuits and Negative Valence Systems in Treatment-Resistant Depression

NCT07166289 | Recruiting DMC

• 1 other identifier: 2024-011
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 1

Brief Summary

Approximately one third of individuals with Major Depressive Disorder (MDD) are considered treatment-resistant, subject to severe disability and risk of suicide, and exhibit symptoms anchored in abnormalities of Research Domain Criteria (RDoC) Negative Valence Systems behavioral processes. In the present study we plan to use low-intensity focused ultrasound in 120 persons with treatment-resistant MDD to modulate deep white matter tracts connecting the thalamus and different regions of the prefrontal cortex reversibly and non-invasively, with the aim of assigning a causal, mechanistic role to large scale brain circuits in the production of those critical behavioral abnormalities. A successful study will help to attain the precise definition of neuromodulation targets for this clinical population in utter need of help.

Conditions

Treatment-Resistant Depression

Keywords

Treatment-Resistant Depression; Low-Intensity Focused Ultrasound

Outcome Measures

Primary Outcomes (2)

• Post-Sonication Changes in Functional Connectivity

  Changes in resting-state functional (fMRI) connectivity (FC) between thalamus and either Anterior Cingulate (ACC) or Orbitofrontal (OFC) cortices after LIFU or Sham stimulation.

  Pre- vs up to 30 minutes post-sonication or sham intervention.

• Post-Sonication Changes in Reward and Repetitive Mentation

  Changes in BOLD activation of either Anterior Cingulate (ACC) or Orbitofrontal Cortex (OFC) during Monetary Incentive Delay and Induced Rumination Tasks corresponding to changes in reward and repetitive thinking, respectively.

  Up to 30 minutes post-sonication vs sham intervention

Secondary Outcomes (1)

• Post-Sonication Changes in Functional Connectivity and Anhedonic and Ruminative Symptoms

  Pre- vs up to 30 minutes post-sonication

Study Arms (3)

Thalamo-Anterior Cingulate Cortex Tract LIFU Sonication

EXPERIMENTAL

An 80-second train of 20-millisecond bursts of ultrasound (0.5 MHz), repeated every 200 milliseconds (400 bursts). It is estimated a 75% tissue attenuation of energy when the ultrasound wave reaches its target, therefore the investigators 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 estimated derated ISPPA). Any modeling of actual energy delivery will be made a posteriori employing BabelBrain® software embedded in the Brainsight® neuronavigation system.

Other: Low-intensity focused ultrasound

Thalamo- Orbitofrontal Cortex Tract LIFU Sonication

EXPERIMENTAL

An 80-second train of 20-millisecond bursts of ultrasound (0.5 MHz), repeated every 200 milliseconds (400 bursts). It is estimated a 75% tissue attenuation of energy when the ultrasound wave reaches its target, therefore the investigators 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 estimated derated ISPPA). Any modeling of actual energy delivery will be made a posteriori employing BabelBrain® software embedded in the Brainsight® neuronavigation system.

Other: Low-intensity focused ultrasound

Sham LIFU

SHAM COMPARATOR

An 80-second train of 20-millisecond bursts of ultrasound (0.5 MHz), repeated every 200 milliseconds (400 bursts). It is estimated a 75% tissue attenuation of energy when the ultrasound wave reaches its target, therefore the investigators 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 estimated derated ISPPA). Any modeling of actual energy delivery will be made a posteriori employing BabelBrain® software embedded in the Brainsight® neuronavigation system.

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

Sham LIFU; Thalamo- Orbitofrontal Cortex Tract LIFU Sonication; Thalamo-Anterior Cingulate Cortex Tract LIFU Sonication

Eligibility Criteria

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

You may qualify if:

• Persons 18-65 years old, with sex and ethnicity recruitment targets including a M:F proportion of 1:2 and White:Black:Hispanic:Native American proportion as close as possible to 8:2:2:1 to reflect the regional epidemiology of TRD (63% White American; 16% African American; 14% Hispanic of any race; 5% Native American),
• DSM-5-TR diagnosis of MDD as confirmed by MINI structured interview followed by consultation with a board-certified psychiatrist,
• Evidence of treatment resistance defined as continued MDD symptoms despite any of the following:
• two or more adequate (6 week) trials of antidepressants with different mechanisms,
• evidence-based psychotherapy,
• augmentation agent (lithium, atypical antipsychotic, or T3), or
• consideration of ECT or prior ECT nonresponse or intolerance,
• at least moderate symptoms as indicated by MADRS≥20 upon screening
• stable treatments including psychotherapy and medication for at least six weeks prior to participation.
• Fluent English speaker, capable of written consent
• Consent that random observations of pathology are possible (e.g., brain abnormality seen during imaging)

You may not qualify if:

• Clinical history of at least minor neurocognitive disorder of neurodegenerative origin,
• PROMIS (Cognitive Function scale) score ≤40 (i.e., mean - 1SD), collected at baseline
• clinical history of relevant structural pathology of the central nervous system, including Parkinson's disease, multiple sclerosis, and brain malignant neoplasia,
• uncontrolled diabetes mellitus (as evidenced by a fasting glycemia ≥ 120 mg/dL or hemoglobin A1c ≥ 6.5%) or hypertension (as evidenced by two consecutive readings ≥ 140/90 mmHg) to ensure medical stability, collected at baseline
• pregnancy or lactation,
• Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, amphetamine/methamphetamine, and ecstasy), or substance use disorder including alcohol, stimulants, sedatives, and cannabis exceeding mild severity in the last 6 months,
• active suicidal ideation (as measured by Suicide-Risk-Assessment-C-SSRS75 "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 3 months, collected at baseline
• MRI contraindications as detected by the MRI Safety Screen, including unwillingness/unable to complete MRI scans
• medical history indicative of moderate to severe traumatic brain injury as evidenced by history of \> 5 minutes of loss of consciousness, or of skull fractures, which in theory could distort LIFU tissue propagation, and
• a current diagnosis of a psychotic disorder (e.g. schizophrenia, bipolar disorder), an eating disorder (e.g. anorexia or bulimia nervosa), learning disability, or a personality disorder that is considered by the investigator to interfere with the ability of the subject to adhere to the protocol (e.g., narcissistic personality disorder, borderline personality disorder).
• Has a history of moderate or severe substance or alcohol use disorder according to DSM-5-TR
• Use of benzodiazepines or anticonvulsants in the 7 days prior ot screening
• Medical, psychiatric, or other conditions that restrict the patient's following abilities: to interpret the study information, to give informed consent, to adhere to the rules of the protocol, or to complete the study.
• No reliable method of communication (i.e., no access to internet or phone connection)
• Prescription of a medication outside of the accepted range, as determined by best clinical practices and current research

Sponsors & Collaborators

• Laureate Institute for Brain Research, Inc.: lead

Study Sites (1)

Laureate Institute for Brain Research

Tulsa, Oklahoma, 74136, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Central Study Contacts

Salvador M Guinjoan, MD, PhD

CONTACT

918-502-5119; sguinjoan@laureateinstitute.org

Danielle E Clark, MA

CONTACT

918-701-9610; dclark@laureateinstitute.org

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 adverse effects will be blind to the intervention.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2025
• First Posted: September 10, 2025
• Study Start: September 30, 2025
• Primary Completion (Estimated): April 1, 2030
• Study Completion (Estimated): July 1, 2030
• Last Updated: March 2, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)