Resonant Frequency rTMS: A Novel Approach to Target Circuit Modulation in Major Depressive Disorder

NCT06572683 | Enrolling By Invitation FDA Device

• 2 other identifiers: 23-001254R01MH135293
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to develop a more personalized brain stimulation using repetitive transcranial magnetic stimulation or rTMS approach to treat major depressive disorder (MDD). The investigators had previously developed a personalized rTMS treatment by examining the effectiveness of different rTMS frequency from 5 to 18 Hertz (Hz). The optimal treatment frequency is termed resonance frequency and varies across individuals. There has not been a systematic method to identify the best stimulation frequency in an individual-specific way. In this project, the investigators will identify and compare 3 rTMS frequencies, all targeting the brain region called left dorsolateral prefrontal cortex (DLPFC): 1 that engages brain circuit connectivity the most- the investigators call this resonant frequency (RF)-max (RF-max), 1 that is the lowest ranked resonance frequency called RF-min and 1 that is standard of care treatment - rTMS of 10 Hz as a point of comparison. This study is a multi-sites project that will be conducted at UCLA and Butler hospital. This study will enroll 84 participants with MDD over the course of 4.5 years. Participants will undergo a brain imaging scan or magnetic resonance imaging (MRI), 3 electroencephalograms (or EEG, a measurement of electrical activity of the brain), to identify rTMS resonance frequencies (RFs), 3 sessions of different resonant frequencies of rTMS in combination with EEG, totaling up to 7 in person visits. Participation will take up to 4 weeks.

Conditions

MDD; Depression

Keywords

rTMS; TMS; Depression; MDD

Outcome Measures

Primary Outcomes (4)

• Repeatability of the Resonant Frequency measure

  Resonant Frequency (RF) of brain oscillations will be measured three times for each participant. Each time, all unique frequencies will be assigned a ranking corresponding to the degree of elicited network activity. We will then compute pairwise Spearman's correlation coefficients (R) between individual rankings obtained at time 1 (T1) vs time 2 (T2), T1 vs Time 3 (T3), and T2 vs T3. We expect that all R-values will be above R = 0.4. This will be single-subject level analysis.

  1 week per subject (Three RF measurements will happen within 1 week)

• Changes in Electroencephalograms (EEG) functional connectivity

  Electroencephalograms functional connectivity (EEG-FC) will be measured after rTMS stimulation 1) at the maximal and 2) at the minimal RF (RFmax, RFmin, respectively), as derived from the ranking using Outcome Measure 1. We will compare changes in EEG-FC after RFmax to changes in EEG-FC after RFmin. This will be a group-level analysis.

  Ten days for each subject (2 sessions (RFmax/RFmin) separated by one week).

• Spatial maps of source-localized EEG connectivity

  We will quantitatively compare the spatial extend of source-localized connectivity elicited by RFmax vs. RFmix stimulation. Binary statistical connectivity maps will be compared for size and percentage of overlap between the two conditions.

  Ten days for each subject (2 sessions (RFmax/RFmin) separated by one week)

• Percent overlap between spatial maps of source-localized EEG connectivity and fMRI-based MDD-rTMS responsive network

  Similar to Outcome measure 3, but instead of comparing the spatial extend of EEG connectivity between RFmax vs. RFmin, this analysis will quantify the similarity to an MDD-rTMS responsive network derived from functional MRI data (Siddiqi et al. 2020).

  1 week per subject.

Study Arms (1)

Experimental RF

EXPERIMENTAL

All participants will then undergo six 3000-pulse rTMS "treatment" sessions: two at RFMAX (or rTMSRF-MAX), two at RFMIN (or rTMSRF-MIN), and two at 10 Hz in random order.

Device: Transcranial Magnetic Stimulation

Interventions

Transcranial Magnetic Stimulation DEVICE

Transcranial magnetic stimulation (TMS) is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve symptoms of depression. Using pulsed magnetic fields, transcranial magnetic stimulation therapy stimulates the part of the brain thought to be involved with mood regulation. These magnetic fields do not directly affect the whole brain; they only reach about 2-3 centimeters into the brain directly beneath the treatment coil.As these magnetic fields move into the brain, they produce very small electrical currents. These electrical currents activate cells within the brain, causing them to rewire, a process called neuroplasticity.

Experimental RF

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects must be between 21-75 years of age.
• Must have confirmed diagnosis of severe \*Major Depressive Disorder (single or recurrent episode) as confirmed by the Mini-International Neuropsychiatric Interview (MINI) or/and a score of 17 or above on the Hamilton Depression Rating Scale (HAMD).
• Failure to respond to a minimum of 2 trials of antidepressant medication.
• Failure to respond from at least two different agent classes.
• Accompanied by at least two evidence-based augmentation therapies (Benzodiazepines do not count).
• Must have a trial of psychotherapy known to be effective in the treatment of MDD of an adequate frequency and duration.
• Subjects are willing and able to adhere to the treatment schedule and required study visits.
• TMS treatment is clinically-approved only for those suffering from Major Depressive Disorder as their primary diagnosis.

You may not qualify if:

• Are mentally or legally incapacitated, unable to give informed consent
• Have an infection or poor skin condition over the scalp where the device will be positioned.
• Have increased risk of seizure because of family history, stroke, or currently use medications that lead to increased risk for seizure.
• Diagnosis of acute or chronic psychotic symptoms or disorders (such as schizophrenia, schizophreniform or schizoaffective disorder) in the current depressive episode.
• Neurological conditions that include epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, having a history of repetitive or severe head trauma, or with primary or secondary tumors in the central nervous system.
• Presence of an implanted magnetic-sensitive medical device present in the body scan, located less than or equal to 30 centimeters from the transcranial magnetic stimulation magnetic coil or other implanted metal items, including but not limited to a cochlear implant, implanted cardioverter defibrillator, pacemaker, vagus nerve stimulator, or metal aneurysm clips or coils, staples, or stents. (Note: Dental amalgam fillings are not affected by the magnetic field and are acceptable for use with transcranial magnetic stimulation and MRI.)
• Current diagnosis of substance use disorder.

Sponsors & Collaborators

• University of California, Los Angeles: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of California

Los Angeles, California, 90024, United States

Location

MeSH Terms

Conditions

Depression

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Joe Gibbs

  University of California, Los Angeles

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The investigators will identify the participant's individual resonant frequencies (RF) by a series of pulse trains between 5-18 Hz at 0.5 Hz intervals, at a total of 27 unique frequencies, delivered in a random order. The total procedure takes 35 minutes. The investigators will conduct this procedure 3 times over the course of 3 days, 1 procedure per day. The investigators will then determine the optimal resonant frequency by ranking all interrogated frequencies based on their degree of elicited connectivity changes within the defined target circuit. The optimal RF (RFMAX) will be the stimulation frequency that ranks highest with regard to connectivity increase (RFMAX). RFMIN is the lowest ranked frequency. Participants will then undergo six rTMS "treatment" sessions: two at RFMAX, two at RFMIN, two at 10 Hz in random order. The two sessions at the same frequency will be administered on the same day, separated by 1 hour.

Study Record Dates

• First Submitted: August 12, 2024
• First Posted: August 27, 2024
• Study Start: February 12, 2024
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): October 31, 2028
• Last Updated: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Shared data generated from this project will be made available as soon as possible, and no later than at the time of publication or the end of the funding period, whichever comes first. The duration of preservation and sharing of the data will be a minimum of 5 years after the end of the funding period.

Locations

US (1)