Neuromodulation of the Fear Extinction Circuit Using Temporally and Anatomically Specific TMS in Humans

This study aims to explore the mechanisms of how transcranial magnetic stimulation (TMS) impacts fear circuits. The overarching objectives are to understand how varying TMS parameters affect targeted brain regions in order to optimize its impact on enhancing fear extinction memory consolidation in a population with known fear extinction deficiencies: post-traumatic stress disorder (PTSD). 250 subjects will take part in this research study across UTHealth Houston. The study will include preliminary screenings, baseline visits, and experimental visits across four days

Study Overview

• Status: Recruiting
• Conditions: PTSD
• Intervention / Treatment: Device: Transcranial magnetic stimulation (TMS); Behavioral: Fear Conditioning and Extinction Paradigm

Detailed Description

The experiments proposed are aimed to understand how timing and location of transcranial magnetic stimulation (TMS) in humans will impact their ability to reduce conditioned fear responses and impact the activation of their brain regions involved in fear regulation. The researchers will use a novel TMS approach to vary timing and location of its delivery so that the researchers can characterize and establish best time and location to obtain optimal impact on fear inhibition, and then test these parameters in PTSD patients and see if such can rescue extinction deficits in PTSD. The anticipated impact is to enhance our understanding of the neural mechanisms of associated with TMS use and explore potential novel approaches for advancing PTSD treatment.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mohammed Milad, PhD; Phone Number: 713-486-2754; Email: Mohammed.R.Milad@uth.tmc.edu

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77054
      • Recruiting
      • UTHealth Houston
      • Contact: Mohammed R. Milad, MD; Email: Mohammed.R.Milad@uth.tmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Willing and able to provide informed consent.
• Inclusion Criteria for PTSD Subjects - Diagnosis of current PTSD
• Inclusion Criteria: Healthy Controls (HC) - no current psychiatric disorders ("Axis I" disorders)

Exclusion Criteria:

• Lifetime history of seizure or significant head trauma or other significant neurologic disease (e.g., tic disorder)
• History of serious/significant psychiatric diagnoses ("Axis I" diagnoses)
• Current significant suicidal ideation, plan or intent or suicidal behavior in past 6 months based on CSSRS and clinical judgment or Self-injurious behavior that involves suicidal intent, requires medical attention, or occurs daily
• Use of neuroleptics within one year prior to study
• Current substance use
• Pregnancy (to be ruled out by urine β-HCG).
• Metallic implants or devices contraindicating magnetic resonance imaging.
• Currently taking medications that lower the seizure threshold. These include antipsychotics, high dose theophylline or stimulants such as methylphenidate. Patients taking bupropion must be on a stable dose (*last 3 months) and take less than or equal to 300 mg/day.
• Implanted devices in subject's head (shunts, cochlear implants); metal in subject's head (other than dental implants).
• High risk of adverse emotional or behavioral reaction, and/or an inability to understand study procedures or the informed consent process
• Additional exclusion criteria for Healthy controls (HC) group: Current psychiatric diagnosis ("Axis I" diagnosis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Fear Conditioning and Extinction Paradigm, plus Transcranial Magnetic Stimulation (TMS); Participants will undergo a 3-day experimental paradigm. On day 1, participants will undergo a resting-state and structural scans in the fMRI scanner. The data from this scan will be used to determine the specific location of the TMS target for each participant. And participants will be aversively conditioned to two cues in the fMRI scanner. Task based and resting-state scans will occur on this day. On day 2, subjects will undergo extinction training outside of the scanner where one of the conditioned cues will be paired with TMS in a temporally and anatomically specific manner. A resting-state scan will occur before and after inside the scanner. On day 3, conditioned cues will be presented during the extinction recall phase of the study. This phase will be conducted in the fMRI scanner. Task-based and resting-state scans will occur on this day.

Device: Transcranial magnetic stimulation (TMS); Research subjects will undergo non-invasive TMS, with a frequency of 20Hz and intensity of 120% of their resting motor threshold (rMT) at varying time points and locations.; Behavioral: Fear Conditioning and Extinction Paradigm; Participants will undergo a 3-day experimental paradigm. On day 1, participants will undergo a resting-state and structural scans in the fMRI scanner. The data from this scan will be used to determine the specific location of the TMS target for each participant. And participants will be aversively conditioned to two cues in the fMRI scanner. Task based and resting-state scans will occur on this day. On day 2, subjects will undergo extinction training outside of the scanner where one of the conditioned cues will be paired with TMS in a temporally and anatomically specific manner. A resting-state scan will occur before and after inside the scanner. On day 3, conditioned cues will be presented during the extinction recall phase of the study. This phase will be conducted in the fMRI scanner. Task-based and resting-state scans will occur on this day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skin Conductance Response (SCR)	Conductance is measured by placing two electrodes next to the skin and passing a tiny electric charge between the two points. SCR is proportionally related to the number of sweat glands that are activated, meaning in essence that the more emotionally aroused an individual is, the more the SCR amount is increased.	Experimental Day 1
Skin Conductance Response (SCR)	Conductance is measured by placing two electrodes next to the skin and passing a tiny electric charge between the two points. SCR is proportionally related to the number of sweat glands that are activated, meaning in essence that the more emotionally aroused an individual is, the more the SCR amount is increased.	Experimental Day 3
Functional MRI (fMRI) blood-oxygen-level-dependent (BOLD) responses	fMRI data, including blood-oxygen-level-dependent (BOLD) responses, is used in neuroimaging studies assess neural correlate activations and observe the increase/decrease in activation of a particular brain area in response to a specific cue. When these cells are active, there is an increase in blood oxygen in the surrounding area.	Experimental Day 1
Functional MRI (fMRI) blood-oxygen-level-dependent (BOLD) responses	fMRI data, including blood-oxygen-level-dependent (BOLD) responses, is used in neuroimaging studies assess neural correlate activations and observe the increase/decrease in activation of a particular brain area in response to a specific cue. When these cells are active, there is an increase in blood oxygen in the surrounding area.	Experimental Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Score on State-Trait Anxiety Inventory (STAI) - Form Y1	STAI - Form Y1 is a commonly used measure of trait and state anxiety that consists of 20 statements that describe oneself. Each statement is scored from 1 (Not at all) to 4 (very much so). The total score range is 20-80. STAI scores are commonly classified as "no or low anxiety" (20-37), "moderate anxiety" (38-44), and "high anxiety" (45-80).	Experimental Day 1
Score on State-Trait Anxiety Inventory (STAI) - Form Y1	STAI - Form Y1 is a commonly used measure of trait and state anxiety that consists of 20 statements that describe oneself. Each statement is scored from 1 (Not at all) to 4 (very much so). The total score range is 20-80. STAI scores are commonly classified as "no or low anxiety" (20-37), "moderate anxiety" (38-44), and "high anxiety" (45-80).	Experimental Day 3

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Mohammed Milad, PhD, The University of Texas Health Science Center at Houston (UTHealth Houston)

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: May 5, 2022
• First Submitted That Met QC Criteria: May 5, 2022
• First Posted (Actual): May 10, 2022

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Mental Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: HSC-MS-23-0426; R01MH125198 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• IPD Sharing Access Criteria: The investigator who proposed to use the data.Upon reasonable request. Requests should be directed to Mohammed.R.Milad@uth.tmc.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

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