TMS Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers

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

Study Overview

• Status: Terminated
• Conditions: Autism
• Intervention / Treatment: Drug: R-baclofen

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).

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Berenson-Allen Center for Noninvansive Brain Stimulation Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: sugar pill; placebo administered under double blind conditions	Drug: R-baclofen; oral R-baclofen at 0x2, 3, 10, and 25 mg; Other Names: arbaclofen
Experimental: 3 mg of R-baclofen; 3 mg of R-Baclofen administered double blind	Drug: R-baclofen; oral R-baclofen at 0x2, 3, 10, and 25 mg; Other Names: arbaclofen
Experimental: 10 mg of R-baclofen; 10 mg of R-baclofen administered double-blind	Drug: R-baclofen; oral R-baclofen at 0x2, 3, 10, and 25 mg; Other Names: arbaclofen
Experimental: 25 mg of R-baclofen; 25 mg of R-baclofen administered double blind	Drug: R-baclofen; oral R-baclofen at 0x2, 3, 10, and 25 mg; Other Names: arbaclofen
Placebo Comparator: second sugar pill; the second placebo administered double blind	Drug: R-baclofen; oral R-baclofen at 0x2, 3, 10, and 25 mg; Other Names: arbaclofen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD)	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.	at 90 minutes after study drug dose

Collaborators and Investigators

• Sponsor: Gonzalez-Heydrich, Joseph, M.D.
• Collaborators: Boston Children's Hospital; Seaside Therapeutics, Inc.
• Investigators: Study Director: Joseph Gonzalez-Heydrich, MD, Boston Children's Hospital; Study Chair: Alvaro Pascual-Leone, M.D. Ph. D., Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC; Principal Investigator: Lindsay M Oberman, Ph. D, Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: July 28, 2010
• First Submitted That Met QC Criteria: July 28, 2010
• First Posted (Estimate): July 29, 2010

Study Record Updates

• Last Update Posted (Estimate): August 21, 2015
• Last Update Submitted That Met QC Criteria: August 20, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: biomarker; autism; TMS; inhibitory; transcranial magnetic stimulation; plasticity; excitatory; synaptic plasticity; R-Baclofen
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; GABA Agents; Neuromuscular Agents; Muscle Relaxants, Central; GABA Agonists; GABA-B Receptor Agonists; Baclofen
• Other Study ID Numbers: TMS_biomarker_Rbac_normals1