Does rTMS Induce Synaptic Plasticity?

Study Overview
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Brief Summary
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The purpose of this study is to utilize the radioactive positron emission tomography (PET) tracer [11C]UCB-J to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on synaptic plasticity. UCB-J has been validated as a marker for synaptic density. We will use this tracer to examine if rTMS leads to changes in synaptic plasticity, specifically changes in synaptic density, in individuals receiving rTMS for MDD. If rTMS is proven effective for increasing synaptic plasticity, there is a significant potential of a new applicable treatment for a variety of diseases that affect brain physiology.

Detailed Description
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The objective of this project is to discover the neural mechanisms by which Major Depressive Disorder (MDD) is treated, so that we may gain insights into its pathophysiology, as well as to develop new biomarkers. We will utilize the PET tracer [11C]UCB-J, the first in human tracer of neural synapses, to test the hypothesis that the successful treatment of MDD with repetitive Transcranial Magnetic Stimulation (rTMS) is associated with increased synaptic density. We will use this tracer to measure synaptic density before and after rTMS treatment and compare change in synaptic density between subjects who respond to the rTMS treatment and those who do not respond to treatment. The finding of a marked increase in synaptic density in participants who respond to rTMS treatment would point to the possibility of developing new treatments with the potential to modify disease through mitigating, preventing or remediating synaptic loss.

Official Title
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Does Repetitive Transcranial Magnetic Stimulation (rTMS) Induce Synaptic Plasticity?

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: [11C]UCB-J radiotracer
* Device: PET-MR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-70 years in age U.S. Veteran Diagnosis of MDD On a stable medication regimen for at least two weeks prior to testing Stable social environment and housing to enable regular attendance at clinic visits Ability to undergo cognitive testing, clinical assessments, and PET/MR scans Stable medical health Will undergo rTMS treatment for MDD at the VA Palo Alto Able to complete a PET-MR scan without the use of sedation Exclusion Criteria: Active substance use within three months of testing IQ < 70 Major medical neurological illness or significant head trauma Pregnancy or breastfeeding Contraindication to MR scanning, including magnetic-resonance incompatible metal or hardware including pacemakers, cochlear implants, and bullets near a critical organ Weight > 350 lbs or a large body habitus that MR scanner cannot accommodate History of or current claustrophobia Inability to comply with basic study requirements such as following directions and punctuality Acute or unstable chronic medical illness that would affect participation or compliance with study procedures, e.g. unstable angina Unstable psychiatric symptoms that precludes consistent participation in the study, e.g. active current suicidal intent or plan, severe psychosis Inability to undergo PET/MR scan, e.g. claustrophobia, presence of ferromagnetic objects in subject's body

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Major Depression Disorder Participants<br>Participants will undergo positron emission tomography-magnetic resonance (PET-MR) imaging using the [11C]UCB-J radiotracer before and after Repetitive Transcranial Magnetic Stimulation (rTMS) treatment | Drug: [11C]UCB-J radiotracer<br>* I.V. bolus administration of up to 15 mCi (equivalent to 0.3 rems) in the antecubital vein per injection<br>* Other names: C11-UCB-J;Device: PET-MR<br>* Positron emission tomography and magnetic resonance imaging, with a scan duration of up to 120 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Synaptic Density Quantified by Regional Binding Potential (BP_ND) | Synaptic density change (Baseline minus Post Treatment) will be quantified between treatment responsive patients and treatment unresponsive patients with the regional binding potential (BP_ND), a measure of [11C]UCB-J binding. BP_ND will be derived by using the simplified reference tissue model and the centrum semiovale as the reference region. This method has been recently utilized by other investigators in neuropsychiatric samples. Both exploratory voxel-wise BP_ND and region of interest (ROI) BP_ND will be compared across groups. ROIs include the striatum, dorsolateral prefrontal cortex, hippocampus, and superior temporal cortex. | Assessed during PET scans before and after rTMS therapy (90 minutes per scan) |