Role of GABAergic Transmission in Auditory Processing in Autism Spectrum Disorder

  • STATUS
    Recruiting
  • End date
    Jun 30, 2023
  • participants needed
    106
  • sponsor
    National Institute of Mental Health (NIMH)
Updated on 23 November 2021
Accepts healthy volunteers

Summary

Background

Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome. Researchers think brain development may be controlled by gamma-aminobutyric acid (GABA). They want to learn how abnormalities in the GABA system may contribute to ASD.

Objective

To see if repetitive transcranial magnetic stimulation (rTMS) creates short-term changes in how different parts of the brain communicate.

Eligibility

Right-handed people ages 14-17 with ASD, and healthy volunteers ages 18-25.

Design

Participants will be screened with:

Medical history

Physical exam

Medicine review

Neurological exam

Psychological tests and rating scales

Forms and surveys.

Participants will have a hearing test and ear exam.

Participants will have magnetic resonance imaging (MRI) of the brain. They will lie on a table that moves in and out of the MRI scanner. They may look at a screen while in the scanner. A coil will be placed over their head.

Participants will have magnetic resonance spectroscopy. It takes pictures of chemicals in the brain using the MRI scanner.

Participants will have magnetoencephalography. They will sit in a chair. A helmet with magnetic field sensors will be placed on their head.

Participants will have TMS. A wire coil will be held on their scalp. A brief electrical current will pass through the coil.

Participants will have electromyography. Sticky pad electrodes will be placed on the skin during TMS. The electrical activity of their muscles will be measured.

Participants will have rTMS. It uses short bursts of magnetic pulses to affect brain activity.

ASD participants will have 6 visits over 6-8 weeks. Healthy volunteers will have 3 visits over 3-4 weeks....

Description

Study Description:

This will be a within-subject, controlled, proof-of-mechanism study.

Objectives

The study aims to evaluate the relationship between local GABA concentration, structural and functional network connectivity and MEG measures of auditory and language processing in adolescents with ASD and the acute impact of a single session of continuous theta burst stimulation over left posterior superior temporal cortex (pSTC) on these measures. We hypothesize that GABA concentrations, DTI measures of tissue microstructure and fcMRI obtained BOLD correlations within the language network will significantly contribute to the prediction model for MEG indices of auditory and language processing. Participation in the study involves six study visits.

Primary Objective: The overall goal of the current study is to 1) Characterize the relationship between an individual's baseline local cortical GABA concentration, DTI measures of auditory and language network tissue microstructure, and fcMRI indices of local and long-range network functional connectivity (predictor variables) and MEG indices of auditory and language processing (dependent variables).

Secondary Objectives: 2) Evaluate the impact of a single session of cTBS over the left pSTC on these MRS and MEG indices in adolescents (age 14-17) with ASD.

Endpoints

Primary Endpoints:

  1. MEG: Evoked fields and Spectral Power
  2. MRS: GABA+/Cr concentrations in the left pSTC
  3. DTI: Diffusion tensor derived parameters in the auditory radiations and arcuate fasciculus.
  4. fcMRI: BOLD correlations across pre-defined ROIs.

Secondary Endpoints:

  1. MEG: Inter-trial gamma-band coherence (ITC) and resting state alpha to gamma phase-amplitude coupling.
  2. SRS-2, CELF-5, EVT, PPVT, ADOS-2, ADI-R, VABS-III, WASI- II.

Study Population:

In the pilot phase of the study, we aim to enroll up to 20 healthy control adult participants. These healthy control young adult participants (age 18-25) will undergo imaging scans, cTBS, and MEG. They will additionally receive a medical history, brief neurological and physical exam; and complete an IQ assessment and the SRS-2 self-report. As the aim of the healthy control young adult portion of the study involves piloting procedures and tasks and confirming target engagement of active stimulation, the healthy control young adults participation will involve only 4 visits: Two enrollment/screening/baseline visit and two cTBS visits (one with MRS/fMRI immediately before and after and one with MEG immediately before and after).As with the main phase of the study, the visits may be split up to shorten the length of session and limit fatigue. Visits will be scheduled about once a week. All visits must be completed within six months of the date of enrollment.

In the main phase of the study, we aim to collect a sample of 55 adolescents age 14-17 with ASD with complete data. In order to account for screen failures and participant attrition, we will recruit a total of 86 individuals (56% above the goal enrollment).

Phase: N/A

Description of Sites/Facilities Enrolling Participants:

All visits will be outpatient and take place in the Clinical Center (Building 10) on NIH campus.

Description of Study Intervention:

Continuous theta burst stimulation (cTBS) will be applied using a MagPro X100 (MagVenture, Inc. Alpharetta, GA). The cTBS protocol consists of bursts of three pulses of 50 Hz stimulation repeated at 200 ms intervals (5 times per second) for 40 seconds (for a total of 600 pulses). Stimulation will be applied at an intensity of 80% of active motor threshold (AMT). Brainsight (Rogue Research) frameless neuronavigation system will be used to target the specific structural MRI-defined region of stimulation.

Study Duration: 36 months

Participant Duration: 2 months

Details
Condition Pervasive developmental disorder, Autism Spectrum Disorder, autism spectrum disorders
Treatment transcranial magnetic stimulation, continuous theta burst stimulation
Clinical Study IdentifierNCT04798274
SponsorNational Institute of Mental Health (NIMH)
Last Modified on23 November 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Pilot Phase
Inclusion criteria
Ability to provide informed consent
Age: 18-25 years
Must meet the definition of Healthy Control having completed the screening assessment under protocol 01-M-0254, The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers or under protocol 17-M-0181, Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies
Main Study Phase
Inclusion criteria
Ability to provide informed assent and parent consent
Age: 14-17 years
Community Diagnosis of ASD based on DSM-IV or DSM-5 criteria
Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II). WASI-II will be used as a measure of intellectual function. Children will be included when FSIQ > 70\
Right-handed: to reduce heterogeneity
Hearing: Normal hearing in order to complete the behavioural assessments

Exclusion Criteria

Participants will be screened to exclude individuals with co-occurring
neurological or medical conditions that might confound the results, as well as
to exclude subjects in whom MRI or rTMS might result in increased risk of side
effects or complications. This accounts for the majority of the exclusion
criteria listed
Exclusion criteria
Participants will be screened to exclude individuals with neurological
psychological/behavioral or medical conditions, as well as to exclude subjects
in whom MRI or rTMS might result in increased risk of side effects or
complications. This accounts for the majority of the exclusion criteria
listed
Pilot Phase
Non-English Speakers
Known Neurological Disorder
Known Psychiatric Disorder
Known genetic disorder (e.g., NF1, tuberous sclerosis), acquired neurologic disease (e.g. stroke, tumour), cerebral palsy, history of severe head injury, intracranial pathology or significant dysmorphology
History of fainting spells of unknown or undetermined etiology that might constitute seizures
History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy
Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
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
Pregnancy
Participants who have received rTMS less than 7 days prior to enrollment
Individuals taking GABAergic medications as well as any of the following drugs noted to have significant seizure threshold lowering potential: imipramine, amitriptyline, doxepine, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, (MDMA, ecstasy), phencyclidine (PCP, angel s dust), ketamine, gamma-hydroxybutyrate (GHB), alcohol, theophylline
Individuals for whom it is not safe or appropriate to remain on a stable pharmacotherapy (for nonexclusionary medications) for six weeks prior to and over the course of their participation in the study
A current NIMH employee or staff or their immediate family member
Main Study Phase
Non-English Speakers
Known genetic disorder (e.g., NF1, tuberous sclerosis), acquired neurologic disease (e.g. stroke, tumour), cerebral palsy, history of severe head injury, intracranial pathology or significant dysmorphology
History of fainting spells of unknown or undetermined etiology that might constitute seizures
History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy
Any progressive (e.g., neurodegenerative) neurological disorder
Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
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
Pregnancy
Participants who have received prior rTMS
Active or History of psychosis, bipolar disorder bipolar disorder, active severe substance use disorders (within the last month), have active suicidal intent or plan as detected on screening instruments or in the investigator team s opinion is likely to attempt suicide within 6 months
Individuals taking GABAergic medications as well as any of the following drugs noted to have significant seizure threshold lowering potential: imipramine, amitriptyline, doxepine, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, (MDMA, ecstasy), phencyclidine (PCP, angel s dust), ketamine, gamma-hydroxybutyrate (GHB), alcohol, theophylline
Individuals for whom it is not safe or appropriate to remain on a stable pharmacotherapy (for nonexclusionary medications) for six weeks prior to and over the course of their participation in the study
A current NIMH employee or staff or their immediate family member
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