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Does rTMS Induce Synaptic Plasticity?

Primary Purpose

Major Depressive Disorder

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
[11C]UCB-J radiotracer
PET-MR
Sponsored by
Davidzon, Guido, M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Major Depressive Disorder

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • VA Palo Alto Health Care System
  • Stanford University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Major Depression Disorder Participants

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

First Posted
March 13, 2020
Last Updated
September 20, 2021
Sponsor
Davidzon, Guido, M.D.
Collaborators
Stanford University
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1. Study Identification

Unique Protocol Identification Number
NCT04311619
Brief Title
Does rTMS Induce Synaptic Plasticity?
Official Title
Does Repetitive Transcranial Magnetic Stimulation (rTMS) Induce Synaptic Plasticity?
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
February 1, 2022 (Anticipated)
Primary Completion Date
February 1, 2024 (Anticipated)
Study Completion Date
February 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Davidzon, Guido, M.D.
Collaborators
Stanford University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Major Depression Disorder Participants
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
[11C]UCB-J radiotracer
Other Intervention Name(s)
C11-UCB-J
Intervention Description
I.V. bolus administration of up to 15 mCi (equivalent to 0.3 rems) in the antecubital vein per injection
Intervention Type
Device
Intervention Name(s)
PET-MR
Intervention Description
Positron emission tomography and magnetic resonance imaging, with a scan duration of up to 120 minutes
Primary Outcome Measure Information:
Title
Change in Synaptic Density Quantified by Regional Binding Potential (BP_ND)
Description
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Coordinator
Phone
650-849-0552
Email
stevelai@stanford.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jong H Yoon, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
VA Palo Alto Health Care System
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
No current plan to share data
Citations:
PubMed Identifier
28792356
Citation
Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, Gallezot JD, Henry S, Hannestad J, Huang Y, Carson RE. Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2018 Nov;38(11):2041-2052. doi: 10.1177/0271678X17724947. Epub 2017 Aug 9.
Results Reference
background
PubMed Identifier
30014145
Citation
Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Oct 1;75(10):1215-1224. doi: 10.1001/jamaneurol.2018.1836.
Results Reference
background
PubMed Identifier
12468889
Citation
Wu Y, Carson RE. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab. 2002 Dec;22(12):1440-52. doi: 10.1097/01.WCB.0000033967.83623.34.
Results Reference
background
PubMed Identifier
26136672
Citation
Chervyakov AV, Chernyavsky AY, Sinitsyn DO, Piradov MA. Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation. Front Hum Neurosci. 2015 Jun 16;9:303. doi: 10.3389/fnhum.2015.00303. eCollection 2015.
Results Reference
background
PubMed Identifier
30948709
Citation
Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, Nabulsi N, Matuskey D, Angarita GA, Pietrzak RH, Duman RS, Sanacora G, Krystal JH, Carson RE, Esterlis I. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019 Apr 4;10(1):1529. doi: 10.1038/s41467-019-09562-7.
Results Reference
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Does rTMS Induce Synaptic Plasticity?

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