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Role of GABAergic Transmission in Auditory Processing in Autism Spectrum Disorder

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ClinicalTrials.gov Identifier: NCT04798274
Recruitment Status : Recruiting
First Posted : March 15, 2021
Last Update Posted : August 22, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Brief 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....


Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Device: Continuous Theta Burst Stimulation Not Applicable

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Role of GABAergic Transmission in Auditory Processing in Autism Spectrum Disorder
Actual Study Start Date : June 15, 2021
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Active cTBS
This intervention involves active repetitive magnetic stimulation. The coil emits a magnetic field
Device: Continuous Theta Burst Stimulation
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.

Sham Comparator: Sham cTBS
This intervention involves sham (placebo) repetitive transcranial magnetic stimulation. The coil is blinded, but does not emit any magnetic field
Device: Continuous Theta Burst Stimulation
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.




Primary Outcome Measures :
  1. MRS [ Time Frame: immediately pre and post rTMS ]
    GABA+/Cr concentrations in the left pSTC

  2. MEG [ Time Frame: immediately pre and post rTMS ]
    Evoked fields and Spectral Power

  3. fcMRI [ Time Frame: immediately pre and post rTMS ]
    BOLD correlations across pre-defined ROIs.

  4. DTI [ Time Frame: immediately pre and post rTMS ]
    Diffusion tensor derived parameters in the auditory radiations and arcuate fasciculus.


Secondary Outcome Measures :
  1. Neuropsychological Assessments [ Time Frame: Baseline ]
    SRS-2, CELF-5, EVT, PPVT, ADOS-2, ADI-R, VABS-III, WASI-II.

  2. MEG [ Time Frame: immediately pre and post rTMS ]
    Inter-trial gamma-band coherence (ITC) and resting state alpha to gamma phase-amplitude coupling.



Information from the National Library of Medicine

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Ages Eligible for Study:   14 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

Pilot Phase

Inclusion criteria

  1. Ability to provide informed consent
  2. Age: 18-25 years
  3. 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

  1. Ability to provide informed assent and parent consent
  2. Age: 14-17 years
  3. Community Diagnosis of ASD based on DSM-IV or DSM-5 criteria
  4. 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.
  5. Right-handed: to reduce heterogeneity.
  6. Hearing: Normal hearing in order to complete the behavioural assessments.

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

  1. Non-English Speakers
  2. Known Neurological Disorder
  3. Known Psychiatric Disorder
  4. Known genetic disorder (e.g., NF1, tuberous sclerosis), acquired neurologic disease (e.g. stroke, tumour), cerebral palsy, intracranial pathology or significant dysmorphology;
  5. History of fainting spells of unknown or undetermined etiology that might constitute seizures;
  6. History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy;
  7. Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.);
  8. Past or Current History of Tinnitus
  9. Any implant, prosthesis or other permanent alteration of the body that, in the opinion of the investigator, would be unsafe with MRI or TMS or that would produce an artifact that would compromise the integrity of data;
  10. Signs of increased intracranial pressure;
  11. Intracranial lesion (including incidental finding on MRI) that, in the opinion of the investigator, would be unsafe with MRI or TMS or that would produce an artifact that would compromise the integrity of data;
  12. History of any head trauma within 6 months of screening, or beyond 6 months prior to screening, history of head trauma with evidence of traumatic abnormality appearing on a brain scan, or with loss of consciousness >5 minutes, or with other sequelae, excluding headache, lasting > 24 hours.
  13. Pregnancy;
  14. Participants who have received rTMS less than 7 days prior to enrollment;
  15. Individuals currently taking GABAergic medications or any other medication that, in the opinion of the investigator, significantly lowers seizure threshold;
  16. 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;
  17. A current NIMH employee or staff or their immediate family member.

Main Study Phase

  1. Non-English Speakers
  2. Known genetic disorder (e.g., NF1, tuberous sclerosis), acquired neurologic disease (e.g. stroke, tumour), cerebral palsy, intracranial pathology or significant dysmorphology;
  3. History of fainting spells of unknown or undetermined etiology that might constitute seizures;
  4. History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy;
  5. Any progressive (e.g., neurodegenerative) neurological disorder;
  6. Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.);
  7. Past or Current History of Tinnitus
  8. Any implant, prosthesis or other permanent alteration of the body that, in the opinion of the investigator, would be unsafe with MRI or TMS or that would produce an artifact that would compromise the integrity of data;
  9. Signs of increased intracranial pressure;
  10. Intracranial lesion (including incidental finding on MRI) that, in the opinion of the investigator, would be unsafe with MRI or TMS or that would produce an artifact that would compromise the integrity of data ;
  11. <TAB>History of any head trauma within 6 months of screening, or beyond 6 months prior to screening, history of head trauma with evidence of traumatic abnormality appearing on a brain scan, or with loss of consciousness >5 minutes, or with other sequelae, excluding headache, lasting > 24 hours.
  12. Pregnancy;
  13. Participants who have received prior rTMS;
  14. Active or History of psychosis, 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;
  15. Individuals currently taking GABAergic medications or any other medication that, in the opinion of the investigator, significantly lowers seizure threshold.
  16. 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.
  17. A current NIMH employee or staff or their immediate family member.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04798274


Contacts
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Contact: Lindsay M Oberman (301) 435-7962 lindsay.oberman@nih.gov
Contact: Sarah H Lisanby, M.D. (301) 339-4831 lisanbysh@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Sarah H Lisanby, M.D. National Institute of Mental Health (NIMH)
Additional Information:
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Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT04798274    
Other Study ID Numbers: 200159
20-M-0159
First Posted: March 15, 2021    Key Record Dates
Last Update Posted: August 22, 2022
Last Verified: August 18, 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
GABA
Language
ASD
MEG
MRS
Additional relevant MeSH terms:
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Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders