Amygdala Memory Enhancement

Study Overview
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Brief Summary
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The objective is to understand how amygdala activation affects other medial temporal lobe structures to prioritize long-term memories. The project is relevant to disorders of memory and to disorders involving affect and memory, including traumatic brain injury and post-traumatic stress disorder.

Detailed Description
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Direct electrical stimulation (DES) of the basolateral complex of the amygdala (BLA) can improve declarative memory, reflecting the role of the BLA in modulating memory processes in medial temporal lobe (MTL) regions as a function of emotional arousal. Thus, DES can reveal mechanisms of BLA-mediated memory enhancement relevant to human mental health and disease. DES of the BLA can be used to interrogate the function of memory circuits, especially how neuronal oscillations in the MTL support declarative memory. First, BLA is hypothesized to wield the capacity to prioritize long-term retention of information initially encountered adjacent in time over days and weeks after encoding. Second, the BLA preferentially projects to anterior MTL regions and thus is hypothesized to preferentially modulate memory processes in those anatomic regions, processes thought to support memory for non-spatial items more so than memory for spatial locations. Third, although emotional arousal, amygdala activity, MTL activity, and memory performance are typically correlated, the investigators hypothesize that DES will reveal that BLA outputs to other MTL regions cause improved memory performance by directly eliciting pro-memory oscillatory states in those networks. The expected outcomes represent a significant advancement for the basic science of normal memory function and significant movement towards novel therapeutics designed to emulate endogenous mechanisms of memory enhancement.

Official Title
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Mechanisms of Amygdala-Mediated Memory Enhancement in Humans

Conditions
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Brain Diseases, Epilepsy, Memory Disorders, Traumatic Brain Injury, Cognitive Impairment, Post Traumatic Stress Disorder

Intervention / Treatment
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* Device: Intracranial Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be able to understand and speak English. Able to provide informed consent. Diagnosed with epilepsy. Scheduled to undergo long-term intra-cranial video monitoring for seizure onset localization. Must be implanted with intracranial depth electrodes to the left or right amygdala, hippocampus, and parahippocampal/perirhinal cortices. Exclusion Criteria: Unable to understand and speak English. Unable to provide informed consent. Not diagnosed with epilepsy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brain Stimulation<br>Neurosurgical epilepsy patients that undergo placement of medial temporal electrode for seizure localizations will be recruited. All participants will view a series of images of emotionally-neutral objects on a computer screen. After each item presentation, they will randomly undergo either active-BLAES or sham-stimulation. Over subsequent days, free recall and recognition memory for these items, relative to new distractor items will be tested. Memory for items presented with and without stimulation will be compared. Brain activity recorded in the medial temporal lobe during item presentations will be used to predict subsequent memory. Such good and bad memory states (biomarkers) will be used to perform closed-loop stimulation when bad memory states are detected in order to enhance subsequent memory. | Device: Intracranial Stimulation<br>* Electrodes localized to the BLA will be stimulated with either active-BLAES (0.5-3.5 mA, theta-modulated gamma burst) electrical stimulation for a 1-sec duration immediately following item image presentation or sham-BLAES (zero-amplitude). At later stages of the project, stimulation parameters and timing will be varied and triggered not at random, but by real-time closed-loop analysis of memory biomarkers in the medial temporal lobe.<br>* Other names: Device: SHAM basal lateral amygdala electrical stimulation (Sham-BLAES);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free recall memory discriminability index (proportion recalled) | Proportion of items (objects, associations, and scenes) accurately recalled during the delayed recall trial will be compared with and without BLAES for each participant in a within subject design. Subsets of items may be tested after durations up to a month after initial presentation. | 5 years | 
| Recognition memory discriminability index (proportion recalled) | Proportion of items (objects, associations, and scenes) accurately recognized during the delayed recognition trial will be compared with and without BLAES for each participant in a within subject design. Subsets of items may be tested after durations up to a month after initial presentation. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Location of single pulse evoked potential (SPEP) response to amygdala stimulation | Measured by presence of the evoked potential in different brain subregions (hippocampus, entorhinal cortex, perirhinal cortex, and parahippocampal cortex). | 5 years | 
| Amplitude of SPEP response to amygdala stimulation | Measured in microvolts. | 5 years | 
| Latency of SPEP response to amygdala stimulation | Measured in milliseconds. | 5 years | 
| Local field potential (LFP) of good memory state | Measured by relative power spectral frequency recorded at time of item presentation that predicts accurate subsequent memory performance. | 5 years | 
| LFP of bad memory state | Measured by relative power spectral frequency recorded at the time of item presentation that predicts inaccurate subsequent memory performance | 5 years |