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

Purpose

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:

R-baclofen produces a significant change in TMS measures of LTD and E:I ratio; and
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:

Presence of the BDNF val66met allele will be associated with decreased long-term depression (LTD) of cortical excitability
Polymorphisms of GABA-B receptor genes will be associated with altered magnitude of response to R-baclofen as measured by TMS

Condition	Intervention	Phase
Normal Physiology Biomarker Development Autism	Drug: R-baclofen	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Basic Science
Official Title:	Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers for R-baclofen Effects in Normal Volunteers

Resource links provided by NLM:

MedlinePlus related topics: Autism

Drug Information available for: Baclofen

U.S. FDA Resources

Further study details as provided by Gonzalez-Heydrich, Joseph, M.D.:

Primary Outcome Measures:

percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD) [ Time Frame: at 90 minutes after study drug dose ] [ Designated as safety issue: No ]
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.
brain excitatory:inhibitory ratio (E:I ratio). [ Time Frame: 0, 30 and 60 minutes after adminstration of study drug ] [ Designated as safety issue: No ]
E:I ratio will be measured as the MEP in response to stimulation at 120% of the resting motor threshold divided by the long-interval intracortical inhibition (LICI). LICI will be measured by using a suprathreshold (approximately 120% Resting-motor-threshold (RMT) conditioning stimulus delivered 100 ms prior (CS100) to the test stimulus, which will be set to MEP1 mV or the stimulus required to generate an MEP of 1mv. So that the LICI numerically increases with increasing strength of inhibition, the LICI will be expressed as the percent that MEP was decreased by the conditioning stimulus.

Estimated Enrollment:	30
Study Start Date:	October 2010
Estimated Study Completion Date:	July 2012
Estimated Primary Completion Date:	July 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: sugar pill placebo administered under double blind conditions	Drug: R-baclofen oral R-baclofen at 0x2, 3, 10, and 25 mg Other Name: 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 Name: 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 Name: 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 Name: 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 Name: arbaclofen

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

Ages Eligible for Study:	18 Years to 30 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Age: 18-30
IQ: higher than 85 will be included, as assessed by the Wechsler Abbreviated Scale of Intelligence [Wechsler 1999]. Subtests include Vocabulary, Similarities, Block Design and Matrix Reasoning, from which verbal, nonverbal, and full-scale IQ scores are generated
Normal physical examination at Screening. If abnormal, the finding(s) must be deemed clinically insignificant by the investigator.

Exclusion Criteria:

History of fainting spells of unknown or undetermined etiology that might constitute seizures
History of seizures, diagnosis of epilepsy, or family history of treatment resistant epilepsy
Progressive neurological disorder or focal signs of abnormality on neurological exam as conducted by a neurologist
History of abnormal (epileptiform) EEG.
Subjects who are currently receiving treatment with racemic baclofen
Subjects who have a history of hypersensitivity to racemic baclofen
Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
History of a medical condition that might interfere with the conduct of the study, confounds interpretation of the study results, or endangers their own well-being. This includes, but is not limited to impairment of renal function, evidence or history of malignancy or any significant hematological, endocrine, cardiovascular, respiratory, hepatic, or gastrointestinal disease.
Tinnitus
Possible pregnancy
Metal implants (excluding dental fillings)
Pacemaker
Implanted medication pump
Vagal nerve stimulator
Deep brain stimulator
TENS unit (unless removed completely for the study)
Ventriculo-peritoneal shunt
Signs of increased intracranial pressure
Intracranial lesion (including incidental finding on MRI)
History of head injury resulting in prolonged loss of consciousness
Substance abuse or dependence within the past six months
Intake of one or a combination of the following drugs forms a 'Strong Potential Hazard' for application of rTMS due to their significant seizure threshold lowering potential:

I. Imipramine II. Amitriptyline III. Doxepine IV. Nortriptyline V. Maprotiline VI. Chlorpromazine VII. Clozapine VIII. Foscarnet IX. Ganciclovir X. Ritonavir XI. Amphetamines XII. Cocaine (MDMA, ecstasy) XIII. Phencyclidine (PCP, angel's dust) XIV. Ketamine XV. Gamma-hydroxybutyrate (GHB) XVI. Alcohol XVII. Theophylline.

- Intake of one or a combination of the following drugs forms a 'Relative Hazard' for application of rTMS due to their significant seizure threshold lowering potential: I. Mianserin II. Fluoxetine III. Fluvoxamine IV. Paroxetine V. Sertraline VI. Citalopram VII. Reboxetine VIII. Venlafaxine IX. Duloxetine X. Bupropion XI. Mirtazapine XII. Fluphenazine XIII. Pimozide XIV. Haloperidol XV. Olanzapine XVI. Quetiapine XVII. Aripiprazole XVIII. Ziprasidone XIX. Risperidone XX. Chloroquine XXI. Mefloquine XXII. Imipenem XXIII. Penicillin XXIV. Ampicillin XXV. Cephalosporins XXVI. Metronidazole XXVII. Isoniazid XXVIII. Levofloxacin XXIX. Cyclosporine XXX. Chlorambucil XXXI. Vincristine XXXII. Methotrexate XXXIII. Cytosine arabinoside XXXIV. BCNU XXXV. Lithium XXXVI. Anticholinergics XXXVII. Antihistamines XXXVIII. Sympathomimetics.

The inclusion of a patient on any of the above medication (Relative Hazard) will be carefully evaluated and a decision documented by the medically responsible physician. The risk is dependant on the patient's past medical history, drug dose, speed of dose increase (or decrease), history of recent medication changes or duration of treatment, and combination with other CNS active drugs.

Recent withdrawal from one of the following drugs forms a 'Strong Relative Hazard' for application of rTMS due to the resulting significant seizure threshold lowering potential:
1. Alcohol
2. Barbiturates
3. Benzodiazepines
4. Meprobamate
5. Chloral hydrate
Subjects who, in the Investigator's opinion, might not be suitable for the study
All female participants are required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study. The pregnancy test is administered at the CRC (Clinical Research Center) by registered nurses, and consists in an over-the-counter type test.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01172509

Locations

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

Sponsors and Collaborators

Gonzalez-Heydrich, Joseph, M.D.

Children's Hospital Boston

Seaside Therapeutics, Inc.

Investigators

Study Director:	Joseph Gonzalez-Heydrich, MD	Children's Hospital Boston
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

More Information

No publications provided

Responsible Party:	Gonzalez-Heydrich, Joseph, M.D.
ClinicalTrials.gov Identifier:	NCT01172509 History of Changes
Other Study ID Numbers:	TMS_biomarker_Rbac_normals1
Study First Received:	July 28, 2010
Last Updated:	March 8, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Gonzalez-Heydrich, Joseph, M.D.:

plasticity
excitatory
inhibitory
synaptic plasticity
R-Baclofen

TMS
transcranial magnetic stimulation
biomarker
autism

Additional relevant MeSH terms:

Autistic Disorder
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders
Baclofen
GABA-B Receptor Agonists
GABA Agonists
GABA Agents
Neurotransmitter Agents

Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Muscle Relaxants, Central
Neuromuscular Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on June 18, 2013