Modulating Temporoparietal Junction Mentalizing-Related Activity in Autism Spectrum Disorder (ASD) Using Transcranial Magnetic Stimulation (TMS)

Modulating Temporoparietal Junction Mentalizing-Related Activity in Autism Spectrum Disorder Using Transcranial Magnetic Stimulation

The goal of this observational study is to test the modulation effect of different transcranial magnetic stimulation (TMS) on the neural network supporting our ability to create mental representations of others (also known as mentalizing) in young adults with autism. The main question it aims to answers is can stimulation of the right temporoparietal junction can change brain activity related to mentalizing during social interaction in the stimulation area and other brain areas connected to it. Researchers will compare results to a group of individuals without autism to see if the patterns of neural activity change are similar between the groups.

Participants will undergo assessment of their clinical traits and social skills and baseline MRI scan. They will attend three additional visits that include TMS session and functional MRI scans before and right after TMS.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Diagnostic test: fMRI; Device: rTMS

Detailed Description

All participants will be scheduled for four study sessions that include a baseline and three subsequent sessions that will each include two functional magnetic resonance imaging (fMRI) scans, one pre and one post an rTMS session.

During each fMRI scan, participants will be engaged in intersocial, competitive Domino task that involves mentalizing. rTMS manipulation, administered in a double-blind, counterbalanced fashion, includes one session each of excitatory (intermittent theta-burst stimulation, iTBS), inhibitory (continuous TBS, cTBS), and sham sequences. The rTMS will be guided with individualized electric-field modeling calculated from a structural MRI scan collected on the baseline session. This robust design is necessary to identify the optimal rTMS sequence to engage the right TPJ and the mentalizing network in ASD because firm conclusions about how best to modulate this network cannot be drawn from the few known published reports.

Investigators hypothesize that iTBS will result in increased, while cTBS in decreased MTR neural activity in the mentalizing network, with this being more pronounced in ASD, and sham resulting in no change. Understanding this mechanism will be the first and crucial step in validating rTMS of the right TPJ as a viable neural target to modulate neural circuit, and subsequently to modulate social-communication skills in ASD in future clinical studies. The significance of such a line of research should be considered in the context of the high prevalence of ASD and the dire need of developing effective interventions, especially for adults.

The three rTMS sessions will be compared within-subject and between-groups.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Michal Assaf, MD; Phone Number: 860-545-7792; Email: michal.assaf@hhchealth.org
• Study Contact Backup: Name: Vaughn R Steele, MD; Phone Number: 860-545-7855; Email: vaughn.steele@yale.edu

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Recruiting
      • Olin Neuropsychiatry Research Center (ONRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Estimated full-scale IQ>80
• Right handed
• Fluent in English
• Individual can cooperate with all study's procedures
• No history of neurological disorder (e.g. epilepsy) or neurosurgery
• No major medical condition (e.g. cancer, heart failure)
• No history of significant head injury
• No primary relatives with history of any neurological disorder with a potentially hereditary basis, including epilepsy or MS
• No current use of medications with psychotropic (e.g., benzodiazepines) or anti- or pro-convulsants
• No current substance use (determined by urine screen and breathalyzer in all visits)
• Negative urine pregnancy (women) test at time of MRI scans
• No MR contra-indications (e.g. in-body metal implant, severe claustrophobia)
• No previous participation in our lab in a study including the Domino fMRI task
• For ASD: Stable medication treatment 4 weeks prior to study enrollment
• For Control Group: No current or history of psychiatric disorders, other than simple phobia, and/or primary relatives with ASD

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASD: excitatory, then inhibitory, then sham rTMS; Participants in this group will undergo fMRI pre- and post- rTMS. Each will receive an excitatory, inhibitory and sham rTMS to the right temporoparietal junction (TPJ) on mentalizing task-related (MTR) activity over 4 study visits.	Diagnostic test: fMRI; fMRI will be performed pre- and post-rTMS; Device: rTMS; TMS procedures are scheduled during study sessions 2-4 between the two MRI scans on those days. Because rTMS induces neural changes that last about 1 hour, rTMS will be applied immediately before the second MRI scan on each day. Prior to the TMS visits, target coordinates and orientation vectors will be generated from the MRI data and the e-field models and loaded into Localite along with the participant's reconstructed T1 image. During the visits, the participant's head will be co-registered to the T1 using fiducial points at the Nasion and Tragi. TMS pulses will be delivered, using the Localite software to target and track the optimal orientation calculated with e-field modeling.
Experimental: Typically Developing (TD): excitatory, then inhibitory, then sham rTMS; Participants in this group will undergo fMRI pre- and post- rTMS. Each will receive an excitatory, inhibitory and sham rTMS to the right temporoparietal junction (TPJ) on mentalizing task-related (MTR) activity over 4 study visits.	Diagnostic test: fMRI; fMRI will be performed pre- and post-rTMS; Device: rTMS; TMS procedures are scheduled during study sessions 2-4 between the two MRI scans on those days. Because rTMS induces neural changes that last about 1 hour, rTMS will be applied immediately before the second MRI scan on each day. Prior to the TMS visits, target coordinates and orientation vectors will be generated from the MRI data and the e-field models and loaded into Localite along with the participant's reconstructed T1 image. During the visits, the participant's head will be co-registered to the T1 using fiducial points at the Nasion and Tragi. TMS pulses will be delivered, using the Localite software to target and track the optimal orientation calculated with e-field modeling.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mentalizing Task Related (MTR) neural activity in the mentalizing network	Change in MTR activity in six brain regions, from fMRI scans will be measured pre- to post-rTMS.	during each fMRI, up to 5 hours

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Vaughn Steele, MD, Yale University; Principal Investigator: Michal Assaf, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2024
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: January 9, 2024
• First Posted (Actual): January 19, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Diagnostic Techniques and Procedures; Diagnosis; Tomography; Diagnostic Imaging; Magnetic Resonance Imaging
• Other Study ID Numbers: HHC-2023-0203; R01MH132044 (U.S. NIH Grant/Contract); Assaf 121223 (Other Identifier: Yale); 2000039667 (Other Identifier: Yale IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All investigators are aware of and agree to abide by the principles for sharing research resources, as described by NIH in "Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Programs." Specifically, all data collected in this study, including demographic information, psychiatric, symptom, cognitive and social assessments as well as MRI imaging data, will be shared with the scientific community through the National Institute of Mental Health Data Archive (NDA).
• IPD Sharing Access Criteria: National Institute of Mental Health Data Archive (NDA)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No