TMS Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers
| Status: | Terminated |
|---|---|
| Conditions: | Healthy Studies, Neurology, Psychiatric, Autism |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology, Other |
| Healthy: | No |
| Age Range: | 18 - 30 |
| Updated: | 4/21/2016 |
| Start Date: | October 2010 |
| End Date: | July 2012 |
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
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
The design is a double-blind placebo controlled 5 way crossover trial of a single dose each
of placebo x 2 (0 mg), 3, 10, and 25 mg of R-baclofen followed by plasma levels at 0, 30,
60, 90, and 140 minutes after each dose; and TMS testing at 0, 30, 60, 90 (cTBS application
at 90 minute time point), 95, and then periodically every 5-10 minutes until the MEPs return
to baseline. There will be a total of 7 visits. Patients will come in for a screening visit,
then scheduled to return for 1 baseline visit (cTBS without drug) and 5 crossover visits. At
each crossover visit a venous line will be placed for blood sampling and a single dose of
study drug at one of the five dose levels will be given orally at time 0. There will be a
one-week washout between each of the crossover arms (R-baclofen has a mean Tmax of
approximately 80 minutes and a terminal half life of 4.9 hour).
of placebo x 2 (0 mg), 3, 10, and 25 mg of R-baclofen followed by plasma levels at 0, 30,
60, 90, and 140 minutes after each dose; and TMS testing at 0, 30, 60, 90 (cTBS application
at 90 minute time point), 95, and then periodically every 5-10 minutes until the MEPs return
to baseline. There will be a total of 7 visits. Patients will come in for a screening visit,
then scheduled to return for 1 baseline visit (cTBS without drug) and 5 crossover visits. At
each crossover visit a venous line will be placed for blood sampling and a single dose of
study drug at one of the five dose levels will be given orally at time 0. There will be a
one-week washout between each of the crossover arms (R-baclofen has a mean Tmax of
approximately 80 minutes and a terminal half life of 4.9 hour).
Inclusion Criteria:
- Age: 18-30
- IQ: higher than 85
- Normal physical examination
Exclusion Criteria
- significant medical problems
- ongoing medications
- All female participants are required to have a negative pregnancy test
We found this trial at
1
site
Boston, Massachusetts 02215
Click here to add this to my saved trials
