Targeting Specific Brain Networks to Treat Specific Symptoms in Depression

Study Overview
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Brief Summary
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Repetitive transcranial magnetic stimulation (rTMS) is a way of non-invasively stimulating specific brain networks and is an established treatment for Major Depressive Disorder (MDD). This proposal will reveal network mechanisms of the therapeutic effects of rTMS by investigating how stimulating each network specifically changes network connectivity and behavior. This will be done in a highly individualized manner in depressed and healthy patients, leading to more effective and more individualized treatments for depression.

Detailed Description
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Network models are increasingly invoked to characterize the neurobiological underpinnings of mental illnesses. Dysfunction within specific circuits promotes the formation of specific symptoms. This suggests an opportunity to treat specific symptoms by modulating specific circuits. Repetitive transcranial magnetic stimulation (rTMS) is capable of circuit-specific neuromodulation. It is also an established treatment for Major Depressive Disorder (MDD). Clinical experience suggests that rTMS treats different symptom constructs by stimulating different circuits. However, there remains a critical lack of mechanistic evidence to support putative network mechanisms of rTMS, limiting its ability to treat patients with more personalized and optimized approaches. This mechanistic proposal will first use resting-state functional connectivity (FC) MRI and customized analytic pipelines to characterize functional network topography in healthy and depressed individuals at high resolution.This data will be used to derive rTMS targets functionally situated in discrete prefrontal networks (e.g., control, default, salience, limbic/reward). Next, patients will take part in a within-subject design in which they undergo rTMS to each target on separate days. Each target will be stimulated four times on a given day, and after each stimulation changes will be measured with: (1) REST-BOLD MRI (to assess FC changes), (2) TASK-BOLD MRI (to assess changes in BOLD activation on paradigms validated to test RDoC constructs), (3) state-based questionnaires or (4) neuropsychological tests. This work will facilitate individualized neuromodulation approaches based on network topography. This will pollinate large-scale clinical trials assessing the effects of differential circuit modulation. It will also illuminate circuit-construct relationships across neuropsychiatric disorders.

Official Title
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Probing the Functional and Behavioral Impact of Precision Circuit Modulation in Neuropsychiatric Diseases

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: Intermittent Theta Burst Stimulation (iTBS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for healthy participants: 18-65 years of age Capacity to provide informed consent form to participate in the study Inclusion Criteria for participants with Major Depressive Disorder (MDD): 18-65 years of age Capacity to provide informed consent form to participate in the study Currently in a major depressive episode. Comorbid anxiety disorders and personality disorders will be allowed provided that MDD is the primary diagnosis. Exclusion Criteria for all participants: Meeting criteria, in the past or currently, for bipolar affective disorder, hypomania or mania. Meeting criteria, in the past or currently, for a primary psychotic disorder (e.g., schizophrenia). Neurological conditions with known structural brain lesions, e.g., intracranial masses, multiple sclerosis. Any personal history of seizures or a family history of epilepsy in a first-degree relative. Metal in the body that is ferromagnetic or metallic injury to the eyes. Implanted pacemakers, medication pumps, vagal stimulators, deep brain stimulators, or ventriculoperitoneal shunts, etc. Substance abuse or dependence that is current and active within the last six months, as indicated by self-report (e.g., heroin, cocaine, methamphetamines). Inability to meet the safety criteria for MRI scanning for any other reason. Severe or unstable medical illness. Currently pregnant, as assessed with urine pregnancy test in women of childbearing age.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Within-subject crossover study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DLPFC Salience network target<br>iTBS delivered four times daily to an individually defined salience network representation in left dorsolateral prefrontal cortex (DLPFC). | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* iTBS is a form of non-invasive brain stimulation used to treat depression. It works on the principles of electromagnetic induction.<br>* Other names: Repetitive Transcranial Magnetic Stimulation;|
| Experimental: DLPFC Control network target<br>iTBS delivered four times daily to an individually defined control network representation in left dorsolateral prefrontal cortex (DLPFC). | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* iTBS is a form of non-invasive brain stimulation used to treat depression. It works on the principles of electromagnetic induction.<br>* Other names: Repetitive Transcranial Magnetic Stimulation;|
| Experimental: DLPFC Default network A target<br>iTBS delivered four times daily to an individually defined default network A representation in left dorsolateral prefrontal cortex (DLPFC). | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* iTBS is a form of non-invasive brain stimulation used to treat depression. It works on the principles of electromagnetic induction.<br>* Other names: Repetitive Transcranial Magnetic Stimulation;|
| Experimental: dmPFC Default network B target<br>iTBS delivered four times daily to an individually defined default network B representation in left dorsomedial prefrontal cortex (DMPFC). | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* iTBS is a form of non-invasive brain stimulation used to treat depression. It works on the principles of electromagnetic induction.<br>* Other names: Repetitive Transcranial Magnetic Stimulation;|
| Experimental: vmPFC limbic-reward network target<br>iTBS delivered four times daily to an individually defined reward network representation in left ventromedial prefrontal cortex (vMPFC). | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* iTBS is a form of non-invasive brain stimulation used to treat depression. It works on the principles of electromagnetic induction.<br>* Other names: Repetitive Transcranial Magnetic Stimulation;|
| Sham Comparator: SHAM stimulation<br>SHAM iTBS delivered four times daily to an individually defined SHAM region in left dorsolateral prefrontal cortex (DLPFC). | Device: Intermittent Theta Burst Stimulation (iTBS)<br>* iTBS is a form of non-invasive brain stimulation used to treat depression. It works on the principles of electromagnetic induction.<br>* Other names: Repetitive Transcranial Magnetic Stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting-state functional connectivity (FC) | Changes in connectivity within and between brain networks | 1 hour | 
| Blood oxygenation level dependent (BOLD) activation | Changes in activation resulting from performing a specific functional MRI (fMRI) task | 1 hour | 
| Applied Cognition-General Concerns scale | Subjects rate how statements about cognition and attention apply to them, e.g., Thinking is foggy. Score range is 8-40, with higher scores indicating lesser cognitive concerns. | 10 minutes | 
| Profile of Mood States Tension subscale | Subjects are asked to rate how much certain adjectives about their mood apply to them at that moment, e.g., tense, nervous, shaky. Score range: 0-28, higher scores indicating more tension. | 5 minutes | 
| Profile of Mood States Vigor subscale | Subjects rate how much mood adjectives apply to them at that moment, e.g., full of pep, energetic, vigorous. Score range 0-28, higher scores indicating more vigor. | 5 minutes | 
| Profile of Mood States Dejection subscale | Subjects rate how much mood adjectives apply to them at that moment, e.g., unworthy. Score range 0-28, higher scores indicating higher dejection. | 5 minutes | 
| State Shame and Guilt Scale | Subjects rate how much certain statements apply to them, e.g., I feel regret. Score range is 10-50, higher scores indicate more shame/guilt. | 5-10 minutes | 
| Fawcett-Clark Pleasure Capacity Scale | Subjects anticipate how much they would enjoy a certain scenario, e.g., you sit watching a beautiful sunset in an isolated part of the world. Score range is 36 to 180, higher scores indicate higher pleasure capacity. | 5-10 minutes | 
| Digit-Span Test | Subjects repeat number lists in forward or reverse order (maximum score is 8 forwards and 8 backwards, higher scores indicate better performance). | 5 minutes | 
| Tower of London Task | Subjects plan a series of moves to match a start set to a goal set. | 5-10 minutes | 
| Delayed Match to Sample Task | Subjects match patterns to a recently viewed sample pattern. Score ranges from 0-30, with higher scores indicating better performance. | 5 minutes | 
| The Simon Test | Subjects press different buttons based on incongruent spatial and/or color cues. Scores range from 0-30, with higher scores indicating better performance. | 5 minutes | 
| Face-name Associative Paradigm | Subjects must remember names paired with certain faces (DN-A). Scores range from 0-32, with higher scores indicating better performance. | 30 minutes | 
| Reading the Mind Through the Eyes Test | Subjects judge another person's mental state by looking at pictures of only their eyes. Score ranges from 0-41, higher scores indicate better performance. | 10 minutes |