Individualized Functional Connectivity Targeting in aiTBS for Depression (AINT)

The Role of Individualized Functional Connectivity Targeting in Accelerated Intelligent Neuromodulation Therapy (AINT) for Depression

The goal of this clinical trial is to estimate the importance of neuroimaging in accelerated intermittent theta burst stimulation (aiTBS) for depression. Participants will receive aiTBS treatment, but they will not know if their treatment spot was found with neuroimaging or head measurements.

Study Overview

• Status: Active, not recruiting
• Conditions: Depression; Mood Disorders; Depressive Disorder, Major; Psychiatric Disorder; Mental Disorder
• Intervention / Treatment: Procedure: transcranial magnetic stimulation

Detailed Description

Techniques for modulating human brain networks are rapidly evolving. One of the most exciting new developments is accelerated intermittent theta burst stimulation (aiTBS), a transcranial magnetic stimulation (TMS) protocol that involves multiple daily treatments rather than gold standard once daily treatment. A specific accelerated iTBS protocol called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) was cleared by the FDA in September 2022 based on two pilot studies in which patients with treatment-resistant depression rapidly and robustly improved with SAINT. Many of these patients had been depressed for decades and had not improved with conventional TMS or electroconvulsive therapy. Despite these promising results, two issues may limit SAINT scalability: 1) SAINT has only been tested at a single site in a small number of patients, 2) SAINT has never been tested without individualized resting state functional connectivity (rsfc) targeting, which is not widely available or covered by insurance. In this pilot trial, patients with treatment-resistant depression (n=40) will be randomized to one of two active treatment arms: 1) Real aiTBS with real individualized rsfc targeting, or 2) Real aiTBS with sham individualized rsfc targeting (i.e. conventional TMS targeting based on scalp landmarks). All patients will receive active stimulation, which will facilitate enrollment and reduce ethical concerns about placebo treatment in a vulnerable population when there is existing evidence of treatment efficacy. Patients and clinicians will be blind to group assignment, and blind integrity will be assessed. All patients will undergo MRI scans immediately before treatment and at one month follow up, which aligns with our clinical outcome measures.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
• Primary diagnosis of major depressive disorder per Diagnostic and Statistical Manual (DSM)-V criteria (MINI International Neuropsychiatric Interview)
• >20 on BDI
• >20 on the MADRS 10, 11
• Moderate to severe level of treatment resistance (Maudsley Staging Method)
• Stable antidepressant medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the study (including all follow-up assessments after the 5-day treatment protocol).
• Primary clinician responsible for psychiatric care before, during, and after the trial
• Agreement to lifestyle considerations
• Abstain from becoming pregnant from screening through end of treatment
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, soft drinks, chocolate) throughout treatment
• Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session
• Abstain from tobacco products during treatment day

Exclusion Criteria:

• Active pregnancy as determined by a urine pregnancy test
• Primary psychiatric diagnosis other than major depressive disorder requiring treatment other than comorbid anxiety disorder
• Those who did not respond to electroconvulsive therapy (ECT) after 8 sessions
• Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)
• History of:
• Prior exposure to TMS
• Neurosurgical intervention for depression
• Autism spectrum disorder
• Intellectual disability
• Severe cognitive impairment
• Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion)
• Untreated or insufficiently treated endocrine disorder
• Treatment with investigational drug or intervention during the study period
• Depth-adjusted TMS treatment dose > 65% maximum stimulator output
• ≥ 30% change in MADRS score between screening and baseline
• Anyone presenting with:
• Mania or hypomania
• Psychosis
• Active suicidal ideation or a suicide attempt (defined by C-SSRS) within the past year
• Neurological lesion
• Contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).
• Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Positive urine drug screen for illicit substances
• Severe borderline personality disorder
• Any other condition deemed by the PI to interfere with the study or increase risk to the participant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: real individualized resting state functional connectivity targeting; Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with individualized resting state functional connectivity.	Procedure: transcranial magnetic stimulation; Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation will be administered under the supervision of a physician with TMS expertise. This protocol will be modeled after the FDA cleared Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, but the patented SAINT rsfc targeting algorithm will not be used for either arm.; Other Names: TMS; theta burst stimulation; accelerated intermittent theta burst stimulation; aiTBS
Other: sham individualized resting state functional connectivity targeting; Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with head measurements (i.e., Beam F3)	Procedure: transcranial magnetic stimulation; Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation will be administered under the supervision of a physician with TMS expertise. This protocol will be modeled after the FDA cleared Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, but the patented SAINT rsfc targeting algorithm will not be used for either arm.; Other Names: TMS; theta burst stimulation; accelerated intermittent theta burst stimulation; aiTBS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery-Åsberg Depression Rating Scale (MADRS)	Depression severity rating scale (0-60, higher numbers indicate higher severity). The primary analysis of the primary outcome will be the effect size (i.e., Cohen's d) of imaging-guided accelerated TMS relative to scalp-targeted TMS. This outcome has not changed since the original grant application for this study. Actual group differences will be explored in a secondary analysis of this primary outcome measure. Note added May 2025: The description of the primary outcome measure was clarified. The primary outcome remains unchanged.	one month after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beck Depression Inventory (BDI)	Depression severity rating scales (0-63, higher numbers indicate higher severity)	immediately after treatment ends and at all subsequent timepoints (1 week, 1 month, 3 months, 6 months, 9 months, 12 months)
Quick Inventory of Depressive Symptomatology (QIDS)	Depression severity rating scales (0-27, higher numbers indicate higher severity)	immediately after treatment ends and at all subsequent timepoints (1 week, 1 month, 3 months, 6 months, 9 months, 12 months)
Change in resting state functional connectivity in the depression network	blood oxygen level-dependent (BOLD) signal	one month after treatment
Percentage of screened patients from TMS clinical programs who select the accelerated iTBS trial over routine clinical TMS	Patient preference measure	through study completion, an average of 2 years
Temperament and Character Inventory, Revised 140-item	Psychobiologically-based personality inventory which measures seven personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, cooperativeness, and persistence). For each dimension, this yields a scaled T-score (mean score of 50 with standard deviation of 10). This is an overall estimate of personality traits, and there are no "better" or "worse" traits.	one month after treatment
Emotional Conflict Resolution Task	Computer task measuring accuracy and reaction time	one month after treatment
Learning, Multi-Source Interference Task (MSIT)	Computer task measuring accuracy and reaction time	one month after treatment
Penn Emotion Recognition Task (ER-40)	Computer task measuring accuracy and reaction time	one month after treatment
Death Suicide IAT (DSIAT)	Computer task measuring reaction time	one month after treatment
Beck Anxiety Inventory (BAI)	Anxiety severity rating scale (0-63, higher numbers indicate higher severity)	immediately after treatment ends and at all subsequent timepoints (1 week, 1 month, 3 months, 6 months, 9 months, 12 months)
Montgomery-Åsberg Depression Rating Scale (MADRS)	Depression severity rating scale (0-60, higher numbers indicate higher severity). The primary analysis of the primary outcome will be the effect size of imaging-guided accelerated TMS relative to scalp-targeted TMS. In other words, the "number needed to scan." This outcome has not changed since the original grant application for this study and the data remain blinded at the time of this clarification. Actual group differences will be explored in a secondary analysis of this primary outcome measure.	immediately after treatment ends

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Joseph J Taylor, MD, PhD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2023
• Primary Completion (Actual): March 17, 2025
• Study Completion (Estimated): March 17, 2027

Study Registration Dates

• First Submitted: December 13, 2022
• First Submitted That Met QC Criteria: January 10, 2023
• First Posted (Actual): January 11, 2023

Study Record Updates

• Last Update Posted (Actual): May 29, 2025
• Last Update Submitted That Met QC Criteria: May 23, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: neuroimaging; depression; neuromodulation; TMS; brain stimulation; transcranial magnetic stimulation; functional connectivity; theta burst stimulation; accelerated intermittent theta burst stimulation; transcranial; neuronavigation
• Additional Relevant MeSH Terms: Behavioral Symptoms; Problem Behavior; Depression; Depressive Disorder; Mood Disorders; Mental Disorders; Depressive Disorder, Major
• Other Study ID Numbers: 2022p001650

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: De-identified survey response data and/or neuroimaging data may be shared with collaborators for further analysis.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes