Does rTMS Induce Synaptic Plasticity?

Major Depressive Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04311619
• Other study ID #: 54574
• Status: Suspended
• Phase: Phase 1
• Start date: December 1, 2019
• Est. completion date: February 1, 2025

Study information

• Verified date: November 2023
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 10
• Est. completion date: February 1, 2025
• Est. primary completion date: February 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• [11C]UCB-J radiotracer
I.V. bolus administration of up to 15 mCi (equivalent to 0.3 rems) in the antecubital vein per injection

Device:
• PET-MR
Positron emission tomography and magnetic resonance imaging, with a scan duration of up to 120 minutes

Locations

Country	Name	City	State
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	Stanford University	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Davidzon, Guido, M.D.	Stanford University

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)