Does rTMS Induce Synaptic Plasticity?

Davidzon, Guido, M.D.

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Conditions

Major Depressive Disorder

Interventions

[11C]UCB-J radiotracerDRUG

I.V. bolus administration of up to 15 mCi (equivalent to 0.3 rems) in the antecubital vein per injection

PET-MRDEVICE

Positron emission tomography and magnetic resonance imaging, with a scan duration of up to 120 minutes

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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

Locations (2)

VA Palo Alto Health Care System

Palo Alto, California, United States

Stanford University

Stanford, California, United States

Outcomes

Primary Outcomes

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.

Time frame: Assessed during PET scans before and after rTMS therapy (90 minutes per scan)

Data from ClinicalTrials.gov

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