Fear Extinction
Conditions
Keywords
Fear extinction, Fear conditioning, Amygdala, Prefrontal cortex, Intracranial electrical stimulation, Fear learning, Stereoelectroencephalography, Neuromodulation
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.
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.
Interventions
OTHERDirect 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.
BEHAVIORALFear 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.
Sponsors
Washington University School of Medicine
National Institute of Mental Health (NIMH)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Broadband high-frequency power (70-170 Hz) in amygdala-prefrontal circuits | During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay. | 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. |
| Oscillatory power at the stimulation frequency during intracranial electrical 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 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. |
| Amplitude of cortico-cortical evoked potentials in amygdala-prefrontal circuits | During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay. | 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. |
| Theta/gamma band power in amygdala-prefrontal circuits | During research sessions, up to 2 hours per day for up to 4 days during the participant's hospital stay. | 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. |
| Cross-frequency coupling in 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 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. |
| Skin conductance response amplitude 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. | Skin conductance response (SCR) amplitude will be quantified during fear conditioning and extinction to assess autonomic responses to conditioned stimuli. |
| Pupil diameter 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. | Pupil diameter will be quantified from eye-tracking recordings during fear conditioning and extinction to assess autonomic responses to conditioned stimuli. |
| Button press reaction time 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. | Button press reaction time will be quantified during fear conditioning and extinction to assess behavioral responses to conditioned stimuli. |
| Subjective unpleasantness rating 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Heart rate will be quantified during fear conditioning and extinction to assess autonomic responses to conditioned stimuli. |
Countries
United States
Contacts
CONTACTTao Xie, PhD
CONTACTPeter Brunner, PhD
PRINCIPAL_INVESTIGATORTao Xie, PhD
Washington University School of Medicine
Outcome results
None listed