One-Day cTBS Over the Precuneus

NCT07758010 | Not Yet Recruiting FDA Device

• 1 other identifier: 2026P001989
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn whether two forms of one-day accelerated transcranial magnetic stimulation (TMS) can reduce depressive symptoms in adults with treatment-resistant depression. Treatment-resistant depression is depression that has not improved enough after at least two adequate antidepressant medication treatments. TMS is a non-invasive treatment that uses magnetic pulses to stimulate specific areas of the brain. The main questions this study aims to answer are:

• Does continuous theta-burst stimulation (cTBS) targeting the precuneus reduce depressive symptoms 4 weeks after treatment compared with sham stimulation?
• Does intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex reduce depressive symptoms 4 weeks after treatment compared with sham stimulation? Researchers will compare precuneus cTBS, left dorsolateral prefrontal cortex iTBS, and sham stimulation to determine whether either active treatment reduces depressive symptoms more than sham stimulation. Participants will be randomly assigned to one of the three groups and will not be told which treatment they initially receive. Participants will:
• Complete screening procedures and baseline assessments of depression, rumination, and cognitive function
• Receive 20 sessions of active or sham TMS during one in-person study day
• Complete follow-up assessments 1, 2, 3, and 4 weeks after the intervention
• Report any side effects or medical problems experienced during the study Participants initially assigned to sham stimulation may choose to receive active TMS after completing the 4-week follow-up period. Those who choose this option will receive either precuneus cTBS or left dorsolateral prefrontal cortex iTBS and will complete additional follow-up assessments.

Conditions

Depressive Disorder, Treatment-Resistant; Treatment Resistant Depression (TRD); Treatment Resistant Major Depression Disorder

Keywords

Treatment-resistant depression; Accelerated transcranial magnetic stimulation; Precuneus; Dorsolateral prefrontal cortex; Continuous theta burst stimulation; Intermittent theta burst stimulation

Outcome Measures

Primary Outcomes (1)

• Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 4

  The MADRS is a clinician-administered 10-item scale used to assess the severity of depressive symptoms. Each item is scored from 0 to 6, yielding a total score ranging from 0 to 60. Higher scores indicate greater depressive symptom severity. MADRS total scores will be assessed at baseline and at Weeks 1, 2, 3, and 4 after the intervention. Post-intervention scores will be compared between treatment groups with adjustment for baseline MADRS total score. The primary treatment comparison will be conducted at Week 4.

  Baseline and 1, 2, 3, and 4 weeks after the intervention

Secondary Outcomes (5)

• 17-Item Hamilton Depression Rating Scale (HAM-D-17) Total Score Through Week 4

  Baseline and 1, 2, 3, and 4 weeks after the intervention

• Patient Health Questionnaire-9 (PHQ-9) Total Score Through Week 4

  Baseline and 1, 2, 3, and 4 weeks after the intervention

• Ruminative Responses Scale (RRS) Total Score Through Week 4

  Baseline and 1, 2, 3, and 4 weeks after the intervention

• Montreal Cognitive Assessment (MoCA) Total Score at Week 4

  Baseline and 4 weeks after the intervention

• MGH/McLean Objective Neurocognitive Assessment (MONA) Total Score at Week 4

  Baseline and 4 weeks after the intervention

Study Arms (3)

Precuneus cTBS

EXPERIMENTAL

Participants receive 20 sessions of active continuous theta-burst stimulation (cTBS) targeting the Pz location of the international 10-20 EEG system during a single day. Stimulation is delivered using a double-cone coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 40 seconds, for a total of 12,000 pulses. Session onsets are separated by approximately 30 minutes. If stimulation at 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level.

Device: Precuneus-targeted continuous theta-burst stimulation

Left dlPFC iTBS

EXPERIMENTAL

Participants receive 20 sessions of active intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex during a single day. The target is identified using the Beam F3 method, and stimulation is delivered using a figure-of-eight coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 3 minutes, for a total of 12,000 pulses. Session onsets are separated by approximately 30 minutes. If stimulation at 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level.

Device: Left dorsolateral prefrontal cortex intermittent theta-burst stimulation

Sham TMS

SHAM COMPARATOR

Participants receive 20 sessions of sham TMS at the left dorsolateral prefrontal cortex location identified using the Beam F3 method during a single day. A figure-of-eight coil is inverted so that the active surface faces away from the scalp. The device is operated at 80% of the participant's resting motor threshold, and sham stimulation follows the same stimulation pattern and approximate 3-minute duration as active iTBS. Session onsets are separated by approximately 30 minutes. After completing the Week 4 assessment, participants may enter an optional open-label extension and are randomized to receive active precuneus cTBS or left dlPFC iTBS.

Device: Sham transcranial magnetic stimulation

Interventions

Precuneus-targeted continuous theta-burst stimulation DEVICE

Active continuous theta-burst stimulation is delivered to the Pz location of the international 10-20 EEG system to target the precuneus. Stimulation is administered with a double-cone coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 40 seconds. Participants receive 20 sessions during a single day, for a total of 12,000 pulses, with session onsets separated by approximately 30 minutes. If 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level.

Also known as: Precuneus cTBS, Continuous theta-burst stimulation

Precuneus cTBS

Left dorsolateral prefrontal cortex intermittent theta-burst stimulation DEVICE

Active intermittent theta-burst stimulation is delivered to the left dorsolateral prefrontal cortex. The stimulation target is identified using the Beam F3 method. Stimulation is administered with a figure-of-eight coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 3 minutes. Participants receive 20 sessions during a single day, for a total of 12,000 pulses, with session onsets separated by approximately 30 minutes. If 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level.

Also known as: Left dlPFC iTBS, Intermittent theta-burst stimulation

Left dlPFC iTBS

Sham transcranial magnetic stimulation DEVICE

Sham transcranial magnetic stimulation is administered at the left dorsolateral prefrontal cortex location identified using the Beam F3 method. A figure-of-eight coil is inverted so that the active surface faces away from the scalp. The stimulator is operated at 80% of the participant's resting motor threshold using the same intermittent theta-burst timing and approximate session duration as the active left dorsolateral prefrontal cortex intervention. Participants receive 20 sham sessions during a single day, with session onsets separated by approximately 30 minutes.

Also known as: Sham TMS, Sham intermittent theta-burst stimulation

Sham TMS

Eligibility Criteria

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

You may qualify if:

• Age 18 years or older.
• Able to speak, read, and understand English sufficiently to complete the study assessments and provide informed consent independently.
• Diagnosis of major depressive disorder according to DSM-5-TR criteria, confirmed by a qualified physician.
• Treatment-resistant depression, defined as an inadequate response to at least two adequate trials of antidepressant pharmacotherapy.
• Patient Health Questionnaire-9 (PHQ-9) total score of 10 or higher.

You may not qualify if:

• Any condition identified through TMS safety screening that, in the judgment of a study physician, presents an unacceptable safety risk for TMS. Such conditions may include:
• A history of a serious adverse reaction during TMS treatment.
• A history of seizure.
• A history of stroke.
• A history of serious head injury or neurosurgery.
• Metal in the head outside the mouth, such as shrapnel, surgical clips, or metal fragments.
• An implanted device, such as a cardiac pacemaker, cochlear implant, medical pump, or intracardiac line.
• Frequent or severe headaches.
• Another brain-related condition or an illness that caused brain injury.
• A family history of epilepsy.
• Permanent tattoos on the head or neck.
• Current recreational drug use.
• Current pregnancy or possible pregnancy.
• Use of a medication or combination of medications, a recent medication change, or medication withdrawal that, in the judgment of a study physician, presents an unacceptable safety risk, including a clinically significant increase in seizure risk.
• Current or lifetime diagnosis of bipolar I disorder, bipolar II disorder, a schizophrenia spectrum disorder, or another primary psychotic disorder.

Sponsors & Collaborators

• Mclean Hospital: lead

Study Sites (1)

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

Related Publications (4)

• Sendi M, Halko M, Traynor J, Brown J, Copersino M, Nickerson L, Harnett N, van Rooij S, Pizzagalli D, House S, Beaudoin F, An X, Neylan T, Clifford G, Jovanovic T, Linnstaedt S, Germine L, Bollen K, Rauch S, Haran J, Storrow A, Lewandowski C, Musey P Jr, Hendry P, Sheikh S, Jones C, Punches B, Swor R, Gentile N, Hudak L, Pascual J, Seamon M, Harris E, Pearson C, Peak D, Domeier R, Rathlev N, O'Neil B, Sergot P, Sanchez L, Bruce S, Sheridan J, Harte S, Kessler R, Koenen K, Phelps E, Salat D, Mayberg H, McLean S, Stevens J, Calhoun V, Ressler K, Dillon D. Comprehensive mapping of cognitive and emotion networks in stress, anxiety, and depression implicates the precuneus as a critical hub. Res Sq [Preprint]. 2025 Aug 26:rs.3.rs-7200801. doi: 10.21203/rs.3.rs-7200801/v1.

  PMID: 40909772 BACKGROUND

• Kim H, Halko M, Copersino ML, Traynor J, Dillon D, Sendi M, Razafsha M, Uflacker A, Bharathan AV, Coyle M, Ganesh P, Nolan J, Parlikar RU, Pettibone T, Gunadeva N, Hur KH, Downar J, McGirr A, Ressler K, Brown J. 6 - Depression and Anxiety Symptom Change Following One-Day Ultra-Accelerated TMS Targeting dlPFC or Network-Guided Precuneus: Preliminary Findings. Transcranial Magnetic Stimulation. 2026;7(Suppl 1):100228. doi:10.1016/j.transm.2026.100228

  BACKGROUND

• Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. 2022 Feb;179(2):132-141. doi: 10.1176/appi.ajp.2021.20101429. Epub 2021 Oct 29.

  PMID: 34711062 BACKGROUND

• Vaughn DA, Marino B, Engelbertson A, Dojnov A, Johnson L, Stine M, Vila-Rodriguez F, Weiss N, Nanos G, Downar J. Real-world effectiveness of a single-day regimen for transcranial magnetic stimulation using Optimized, Neuroplasticity-Enhanced techniques in Depression (ONE-D): An open-label case series. Transcranial Magnetic Stimulation. 2025;5:100200. doi:10.1016/j.transm.2025.100200

  BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Central Study Contacts

Hakjoo Kim Kim, Ph.D.

CONTACT

979-777-0679; khj213@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants are masked to treatment assignment during the randomized, sham-controlled phase. The Principal Investigator, who administers TMS and conducts clinical outcome assessments, is not masked to treatment assignment. The designated study team member responsible for randomization is also not masked. Other study personnel, including study physicians, are not informed of treatment assignment during the randomized phase. Masking does not apply to the optional open-label extension.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Postdoctoral Research Fellow

Model Details: During the randomized, sham-controlled phase, participants are assigned in parallel in a 1:1:1 ratio to precuneus cTBS, left dlPFC iTBS, or sham stimulation. After completion of the 4-week randomized phase, participants initially assigned to sham may enter an optional open-label extension and are randomized in a 1:1 ratio to precuneus cTBS or left dlPFC iTBS.

Study Record Dates

• First Submitted: August 6, 2026
• First Posted: August 11, 2026
• Study Start (Estimated): August 24, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: August 11, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)