Amygdala-Prefrontal in Fear Extinction

Causal Dynamics of Human Amygdala-Prefrontal Circuits During Fear Extinction Learning

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.

Study Overview

• Status: Recruiting
• Conditions: Fear Extinction
• Intervention / Treatment: Other: Direct intracranial electrical stimulation; Behavioral: Fear conditioning

Detailed Description

The ability to reduce fear responses through extinction when threats are no longer present is essential for mental health. Deficits in extinction underlie fear-related disorders such as post-traumatic stress disorder (PTSD). A critical gap remains in understanding the neural mechanisms underlying fear extinction, which poses a major barrier to developing more effective therapeutic interventions. The amygdala (AMY)-prefrontal circuits are critical in fear extinction. In animal models, the lateral nucleus of the amygdala (LA) receives sensory inputs and initiates fear learning, while the basal nucleus of the amygdala (BA) integrates regulatory inputs from the ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) for appropriate fear response. However, due to species-specific differences between animal and human neurobiology, the nucleus-specific contributions of the amygdala and their interactions with the vmPFC and dACC in human fear extinction and regulation remain poorly understood. Clinically indicated stereoelectroencephalography (SEEG) electrodes, which allow direct recording and stimulation of amygdala-prefrontal circuits, provide a unique opportunity to address this gap. The objective of this study is to determine the causal dynamics of amygdala-prefrontal circuits involved in fear extinction learning in participants with epilepsy undergoing SEEG monitoring. The study will address three aims: (1) Determine the intrinsic and stimulation-induced dynamics of human amygdala-prefrontal circuits. The study will characterize cause pathways and circuit-level interactions in amygdala-vmPFC-dACC circuits using intracranial recordings and electrical stimulation. (2) Characterize nucleus-specific and hemispherical lateralized dynamics of amygdala-prefrontal circuits during fear extinction. The study will examine the neural dynamics of the LA, BA, and left and right amygdala-prefrontal circuits during fear extinction and regulation. (3) Determine the effects of theta-burst stimulation of amygdala nuclei on fear extinction. Theta-burst stimulation will be applied to the LA and BA during extinction learning to examine how targeted stimulation modulates fear-related neural circuits and behavior.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tao Xie, PhD; Phone Number: 314-747-1443; Email: xiet@wustl.edu
• Study Contact Backup: Name: Peter Brunner, PhD; Phone Number: 314-747-1443; Email: pbrunner@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110-1010
      • Recruiting
      • Washington University School of Medicine
      • Contact: Juliana Amaral Passipieri, PhD; Phone Number: 314-747-1443; Email: ajuliana@wustl.edu
      • Contact: Tao Xie, PhD; Phone Number: 314-747-1443; Email: xiet@wustl.edu
      • Principal Investigator: Tao Xie, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. At least 18 years of age.
2. Able to understand the nature of the task.
3. Able to provide informed consent themselves or provide consent through their legally authorized representative.
4. 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.

Exclusion Criteria:

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

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: Amygdala-prefrontal in Fear Extinction; 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 stimulation; 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.; Behavioral: Fear conditioning; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate during fear conditioning and extinction	Heart rate 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.

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Tao Xie, PhD, Washington University School of Medicine

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): September 15, 2026
• Primary Completion (Estimated): July 31, 2031
• Study Completion (Estimated): July 31, 2032

Study Registration Dates

• First Submitted: August 18, 2026
• First Submitted That Met QC Criteria: August 28, 2026
• First Posted (Actual): September 2, 2026

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 28, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Neuromodulation; Amygdala; Prefrontal cortex; Fear extinction; Stereoelectroencephalography; Fear conditioning; Fear learning; Intracranial electrical stimulation
• Other Study ID Numbers: 202507143; K99MH144521 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No