NCT07800455

Brief Summary

The goal of this clinical trial is to understand how brain circuits involving the amygdala and prefrontal cortex contribute to fear learning and extinction. Fear extinction is the process by which a fear response decreases when a threat is no longer present. The study will include participants with epilepsy who are undergoing stereoelectroencephalography (SEEG) monitoring as part of their clinical care. The main questions this study aims to answer are: How do the amygdala and prefrontal cortex interact during fear learning and extinction? Do different parts and hemispheres of the amygdala have different roles in fear learning and extinction? How does electrical stimulation of the amygdala affect these brain circuits and fear extinction? Participants will complete tasks involving fear learning and extinction while researchers record brain activity from clinically implanted electrodes. Researchers will also use electrical stimulation via these electrodes to study how amygdala activity affects other brain regions and fear extinction.

Trial Health

77
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
40

participants targeted

Target at P25-P50 for not_applicable

Timeline
71mo left

Started Sep 2026

Longer than P75 for not_applicable

Geographic Reach
1 country

1 active site

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress1%
Sep 2026Jul 2032

First Submitted

Initial submission to the registry

August 18, 2026

Completed
15 days until next milestone

First Posted

Study publicly available on registry

September 2, 2026

Completed
13 days until next milestone

Study Start

First participant enrolled

September 15, 2026

Completed
4.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

July 31, 2031

Expected
1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

July 31, 2032

Last Updated

September 2, 2026

Status Verified

August 1, 2026

Enrollment Period

4.9 years

First QC Date

August 18, 2026

Last Update Submit

August 28, 2026

Conditions

Fear Extinction

Keywords

Fear extinctionFear conditioningAmygdalaPrefrontal cortexIntracranial electrical stimulationFear learningStereoelectroencephalographyNeuromodulation

Outcome Measures

Primary Outcomes (9)

  • Broadband high-frequency power (70-170 Hz) in amygdala-prefrontal circuits

    Broadband high-frequency power (70-170 Hz) will be quantified from local field potentials recorded through clinically implanted stereoelectroencephalography (SEEG) electrodes in the amygdala and prefrontal cortex. Broadband high-frequency power will be assessed during fear processing and during intracranial electrical stimulation to characterize local neural activity within amygdala-prefrontal circuits. For stimulation recordings, stimulation artifacts will be removed using appropriate artifact-removal methods, for example, MPARRM (matching pursuit-based artifact reconstruction and removal method) for single-pulse stimulation and LIBRA (linear baseline-integrated removal of artifacts) for high-frequency stimulation.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Oscillatory power at the stimulation frequency during intracranial electrical stimulation

    Oscillatory power at the stimulation frequency will be quantified from local field potentials recorded through clinically implanted stereoelectroencephalography (SEEG) electrodes in the amygdala and prefrontal cortex. Power at the stimulation frequency will be assessed during intracranial electrical stimulation to quantify stimulation-induced oscillatory entrainment within amygdala-prefrontal circuits. For theta-burst stimulation, theta-band activity (4-8 Hz) will be assessed.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Amplitude of cortico-cortical evoked potentials in amygdala-prefrontal circuits

    Cortico-cortical evoked potential (CCEP) amplitude will be quantified from local field potentials recorded through clinically implanted stereoelectroencephalography (SEEG) electrodes following single-pulse intracranial electrical stimulation. CCEP amplitude will be used to assess effective connectivity between the amygdala and prefrontal cortex.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Theta/gamma band power in amygdala-prefrontal circuits

    Theta (4-8 Hz) and gamma (30-50 Hz) band power will be quantified from local field potentials recorded through clinically implanted stereoelectroencephalography (SEEG) electrodes in the amygdala and prefrontal cortex. Theta/gamma-band power will be assessed during fear conditioning and extinction to characterize oscillatory neural activity within amygdala-prefrontal circuits.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Cross-frequency coupling in amygdala-prefrontal circuits

    Cross-frequency coupling will be quantified from local field potentials recorded through clinically implanted stereoelectroencephalography (SEEG) electrodes in the amygdala and prefrontal cortex. Coupling between neural activity across different frequency bands, including phase-amplitude coupling between lower-frequency oscillations and high-frequency activity, will be assessed during resting state and fear processing to characterize cross-frequency neural interactions within amygdala-prefrontal circuits.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Skin conductance response amplitude during fear conditioning and extinction

    Skin conductance response (SCR) amplitude will be quantified during fear conditioning and extinction to assess autonomic responses to conditioned stimuli.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Pupil diameter during fear conditioning and extinction

    Pupil diameter will be quantified from eye-tracking recordings during fear conditioning and extinction to assess autonomic responses to conditioned stimuli.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Button press reaction time during fear conditioning and extinction

    Button press reaction time will be quantified during fear conditioning and extinction to assess behavioral responses to conditioned stimuli.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

  • Subjective unpleasantness rating during fear conditioning and extinction

    Participants will rate the unpleasantness of the conditioned stimuli during fear conditioning and extinction. Ratings will be used to quantify subjective emotional responses to the conditioned stimuli.

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

Secondary Outcomes (1)

  • Heart rate during fear conditioning and extinction

    During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay.

Study Arms (1)

Amygdala-prefrontal in Fear Extinction

EXPERIMENTAL

Participants will undergo direct intracranial electrical stimulation and complete a Pavlovian fear conditioning and extinction task while neural activity is recorded through clinically implanted stereoelectroencephalography (SEEG) electrodes. Electrical stimulation, including single-pulse and/or high-frequency stimulation, will be delivered through the intracranial electrodes to investigate amygdala-prefrontal circuit dynamics. Participants may also receive theta-burst stimulation of the amygdala during extinction learning.

Other: Direct intracranial electrical stimulationBehavioral: Fear conditioning

Interventions

Direct intracranial electrical stimulationOTHER

During a resting state and extinction learning phase, participants will receive electrical stimulation (single-pulse and/or high-frequency stimulation) through the intracranial electrodes while recording local field potentials from the neural networks. Direct electrical stimulation will be accomplished using FDA-approved equipment and stimulation protocols that are consistent with those used routinely for clinical purposes.

Amygdala-prefrontal in Fear Extinction
Fear conditioningBEHAVIORAL

Participants will be involved in a Pavlovian fear conditioning/extinction experiment while recording local field potential signals from the neural networks. During the experiment, neutral stimuli will be paired with an aversive but not painful electric shock (via the surface skin of the hand/foot) or screeching sound.

Amygdala-prefrontal in Fear Extinction

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • At least 18 years of age.
  • Able to understand the nature of the task.
  • Able to provide informed consent themselves or provide consent through their legally authorized representative.
  • Undergoing clinically indicated intracranial electrode implantation with coverage of at least one fear-related brain region, including the amygdala, hippocampus, cingulate cortex, insula, or prefrontal cortex.

You may not qualify if:

  • Under the age of 18.
  • Unable to understand the nature of the task.
  • Unable to provide informed consent themselves or provide consent through their legally authorized representative.
  • No clinically indicated intracranial electrode coverage in any fear-related brain region, including the amygdala, hippocampus, cingulate cortex, insula, or prefrontal cortex

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110-1010, United States

RECRUITING

Related Publications (3)

  • Xie T, Foutz TJ, Adamek M, Swift JR, Inman CS, Manns JR, Leuthardt EC, Willie JT, Brunner P. Single-pulse electrical stimulation artifact removal using the novel matching pursuit-based artifact reconstruction and removal method (MPARRM). J Neural Eng. 2023 Dec 27;20(6):066036. doi: 10.1088/1741-2552/ad1385.

    PMID: 38063368BACKGROUND

  • Xie T, van Rooij SJH, Inman CS, Wang S, Brunner P, Willie JT. The case for hemispheric lateralization of the human amygdala in fear processing. Mol Psychiatry. 2025 May;30(5):2252-2259. doi: 10.1038/s41380-025-02940-2. Epub 2025 Feb 27.

    PMID: 40016388BACKGROUND

  • Xie T, van Rooij SJH, Sun S, Bryson NK, Demarest P, Park H, Maccotta L, Wang S, Brunner P, Willie JT. Right amygdala ablation reduces maladaptive negative interpretation bias and symptoms in a patient with post-traumatic stress disorder. Nat Commun. 2026 Jun 22;17(1):7868. doi: 10.1038/s41467-026-74099-5.

    PMID: 42331801BACKGROUND

Study Officials

  • Tao Xie, PhD

    Washington University School of Medicine

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Tao Xie, PhD

CONTACT

314-747-1443xiet@wustl.edu

Peter Brunner, PhD

CONTACT

314-747-1443pbrunner@wustl.edu

Study Design

Study Type
interventional
Phase
not applicable
Allocation
NA
Masking
NONE
Purpose
BASIC SCIENCE
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

August 18, 2026

First Posted

September 2, 2026

Study Start

September 15, 2026

Primary Completion (Estimated)

July 31, 2031

Study Completion (Estimated)

July 31, 2032

Last Updated

September 2, 2026

Record last verified: 2026-08

Data Sharing

IPD Sharing
Will not share

Locations

US(1)