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Report for Clinical Trial NCT01172509

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers for R-baclofen Effects in Normal Volunteers

Our overall objective is to apply Transcranial Magnetic Stimulation (TMS) to develop measures of human synaptic plasticity and of brain excitatory:inhibitory ratio (E:I ratio), which we propose as novel biomarkers and outcome measures that will expedite clinical trials of treatments for Autism Spectrum Disorder (ASD). One potential therapeutic agent, R-baclofen will be investigated under this protocol. TMS is a safe, inexpensive and noninvasive means to focally stimulate the human brain. Presently, TMS is in extensive use as a means to measure regional brain excitability, which is dependent on local synaptic strength. TMS can be used to temporarily alter synaptic strength as well as to acutely measure levels of cortical excitability and short and long interval inhibition. Since altered synaptic plasticity and an imbalanced inhibitory:excitatory ratio are cited as fundamental abnormalities in ASD, we hypothesize that both severity of ASD-related learning deficits and their improvement after therapy will correlate with TMS measures of synaptic plasticity and E:I ratio. We propose to embed TMS measures of synaptic plasticity and E:I ratio in a 'Proof of Principal' trial of R-baclofen and to examine: Aim 1: Whether R-baclofen (a potential therapeutic agent for ASD) predictably alters TMS measures of synaptic plasticity and E:I ratio as a function of plasma concentration in adult volunteers. We will test the following hypotheses: 1. R-baclofen produces a significant change in TMS measures of LTD and E:I ratio; and 2. R-baclofen plasma levels and TMS measures of LTD and E:I ratio show a predictable exposure-response relationship. Exploratory Aim 1: Whether the presence of genetic polymorphisms of the BDNF and GABA-B receptor genes has a moderating effect on TMS measures and on R-baclofen effects. We will test the following hypotheses: 1. Presence of the BDNF val66met allele will be associated with decreased long-term depression (LTD) of cortical excitability 2. Polymorphisms of GABA-B receptor genes will be associated with altered magnitude of response to R-baclofen as measured by TMS

NCT01172509 Autism

1 Interventions

Name: R-baclofen

Description: oral R-baclofen at 0x2, 3, 10, and 25 mg
Type: Drug
Group Labels: 5

10 mg of R-baclofen 25 mg of R-baclofen 3 mg of R-baclofen second sugar pill sugar pill


Primary Outcomes

Description: Synaptic plasticity or LTD will be measured using the MEP in response to stimulation set at 80% of the active motor threshold. This MEP will be measured at 90 minutes after study drug dose to establish baseline MEP amplitude then LTD will be induced with the cTBS procedure. The amount of LTD remaining at the different time points, post-cTBS will be quantified by measuring the MEPs and dividing it by the baseline MEP. This will yield a percent of baseline MEP at the various time points.

Measure: percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD)

Time: at 90 minutes after study drug dose

Purpose: Basic Science

Allocation: Randomized

Crossover Assignment


There is one SNP

SNPs


1 V66M

We will test the following hypotheses: 1. Presence of the BDNF val66met allele will be associated with decreased long-term depression (LTD) of cortical excitability 2. Polymorphisms of GABA-B receptor genes will be associated with altered magnitude of response to R-baclofen as measured by TMS percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD). --- val66met ---



HPO Nodes