Clinical trial NCT04311619: Does rTMS Induce Synaptic Plasticity?
Official title: Does Repetitive Transcranial Magnetic Stimulation (rTMS) Induce Synaptic Plasticity?
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Major Depressive Disorder
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Stanford University
First posted: 2020-03-17
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Change in Synaptic Density Quantified by Regional Binding Potential (BP_ND)
timeFrame: Assessed during PET scans before and after rTMS therapy (90 minutes per scan)
Secondary outcomes:
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Jong H Yoon, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.