TMS Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers
Status:
Terminated
Trial end date:
2012-07-01
Target enrollment:
Participant gender:
Summary
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
Phase:
Phase 1
Details
Lead Sponsor:
Gonzalez-Heydrich, Joseph, M.D.
Collaborators:
Boston Children's Hospital Boston Children’s Hospital Seaside Therapeutics, Inc.