Clinical trial NCT01172509: TMS Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers
Official title: Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers for R-baclofen Effects in Normal Volunteers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Autism
Keywords: plasticity
excitatory
inhibitory
synaptic plasticity
R-Baclofen
TMS
transcranial magnetic stimulation
biomarker
autism
Lead sponsor: Gonzalez-Heydrich, Joseph, M.D.
Sponsor class: INDIV
Collaborators: name: Boston Children's Hospital
name: Seaside Therapeutics, Inc.
First posted: 2010-07-29
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief 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

Detailed description: 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).

Eligibility criteria: 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

Primary outcomes:
measure: percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD)
timeFrame: at 90 minutes after study drug dose
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Berenson-Allen Center for Noninvansive Brain Stimulation Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Joseph Gonzalez-Heydrich, MD
role: STUDY_DIRECTOR
affiliation: Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
name: Alvaro Pascual-Leone, M.D. Ph. D.
role: STUDY_CHAIR
affiliation: Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
name: Lindsay M Oberman, Ph. D
role: PRINCIPAL_INVESTIGATOR
References: