Individualized Functional Connectivity Targeting in aiTBS for Depression

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Depressive Disorder, Major, Depression, Mood Disorders, Mental Disorder, Psychiatric Disorder

Intervention / Treatment
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* Procedure: transcranial magnetic stimulation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel-group double-blind randomized controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: real individualized resting state functional connectivity targeting<br>Participants in this group will receive aiTBS with neuronavigation to a treatment target identified with individualized resting state functional connectivity. | Procedure: transcranial magnetic stimulation<br>* 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.<br>* Other names: aiTBS;|
| Other: sham individualized resting state functional connectivity targeting<br>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<br>* 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.<br>* Other names: aiTBS;|

What is the study measuring?
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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) | one month after treatment | 

Secondary 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) | immediately after treatment ends | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transcranial magnetic stimulation, accelerated intermittent theta burst stimulation, theta burst stimulation, brain stimulation, neuromodulation, depression, transcranial, TMS, neuronavigation, functional connectivity, neuroimaging