Neuronal Mechanisms of Human Episodic Memory

The purpose the research is to better understand how the human brain accomplishes the basic cognitive tasks of learning new information, recalling stored information, and making decisions or choices about presented information. These investigations are critical to better understand human cognition and to design treatments for disorders of learning and memory.

Study Overview

• Status: Enrolling by invitation
• Conditions: Epilepsy Intractable
• Intervention / Treatment: Behavioral: Cedrus RB-844 response pad; Adtech Behnke-Fried micro-electrodes; Neurolynx electrophysiology system; Blackrock Cerestim stimulator

Detailed Description

The rapid formation of new memories and the recall of old memories to inform decisions is essential for human cognition, but the underlying neural mechanisms remain poorly understood. The long-term goal of this research is a circuit-level understanding of human memory to enable the development of new treatments for the devastating effects of memory disorders. The study experiments utilize the rare opportunity to record in-vivo from human single neurons simultaneously in multiple brain areas in patients undergoing treatment for drug resistant epilepsy. The overall objective is to continue and expand a multi-institutional (Cedars Sinai/Caltech, Johns Hopkins, U Toronto, Children's/Harvard, UC Denver, UCSB), integrated, and multi-disciplinary team. Jointly, the investigators have the expertise and patient volume to test key predictions on the neural substrate of human memory. The study will utilize a combination of (i) in-vivo recordings in awake behaving humans assessing memory strength through confidence ratings, (ii) focal electrical stimulation to test causality, and (iii) computational analysis and modeling.

These techniques will be applied to investigate three overarching hypotheses on the mechanisms of episodic memory. First, to determine the role of persistent neuronal activity in translating working memories into longterm declarative memories (Aim 1). Second, to determine how declarative memories are translated into decisions (Aim 2). Third, to investigate how event segmentation, temporal binding and reinstatement during temporally extended experience facilitate episodic memory.

The expected outcomes of this work are an unprecedented characterization of how episodic memories are formed, retrieved and used for decisions, and how temporally extended experiences are segmented to form distinct but linked episodes. This work is significant because it moves beyond a "parts list" of neurons and brain areas by testing circuit-based hypotheses by simultaneously recording single-neurons from multiple frontal cortical and subcortical temporal lobe areas in humans who are forming, declaring and describing their memories. The proposed work is unusually innovative because it combines single-neuron recordings in multiple areas in behaving humans, develops new methods for non-invasive localization of implanted electrodes and electrical stimulation and directly test long-standing theoretical predictions on the role of evidence accumulation in memory retrieval.

A second significant innovation is the study team, which combines the patient volume and expertise of several major centers to maximally utilize the rare neurosurgical opportunities available to directly study the human nervous system. This innovative approach permits investigation of circuit-level mechanisms of human memory that cannot be studied non-invasively in humans nor in animal models. This integrated multi-disciplinary combination of human in-vivo single-neuron physiology, behavior, and modeling will contribute significantly to the understanding of the circuits and patterns of neural activity that give rise to human memory, which is a central goal of human neuroscience in general and the BRAIN initiative in particular.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Intractable epilepsy, undergoing invasive monitoring
• Age ≥13
• Full Scale Intelligence Quotient > 70
• Ability to comprehend and perform simple behavioral tasks by pressing buttons on laptop computer in response to questions.

Exclusion Criteria:

• Determination by clinicians and investigators that a patient is unable to complete the behavioral tasks required for the protocol due to either cognitive limits, psychological limits, or pain.

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: Behavioral Testing; Behavioral and Neuronal Recordings	Behavioral: Cedrus RB-844 response pad; Adtech Behnke-Fried micro-electrodes; Neurolynx electrophysiology system; Blackrock Cerestim stimulator; Devices listed are components of a single intervention that includes: Record patient responses (Cedrus RB-844), record neuronal activity (Neurolynx) from electrodes (Adtech Behnke-Fried), apply intermittent electrical stimulation (Blackrock Cerestim)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent Neuronal Activity (Firing Rates)	Neuronal firing rates (measured in spike rates per second) of cells in the frontal and temporal lobes during working memory.	3 years
Persistent Neuronal Activity (Power)	Power of local field potential bandwidths (measured in amplitude across frequency of the bandwidths) in the frontal and temporal lobes during working memory.	3 years
Decision Making (Firing Rates)	Neuronal firing rates of cells (measured in spike rates per second) in the frontal and temporal lobes during a decision-making process.	5 years
Decision Making (Power)	Power of local field potential bandwidths (measured in amplitude across frequency of the bandwidths) in the frontal and temporal lobes during a decision-making process.	5 years
Decision Making (Timing)	Timing of neuronal discharges (measured in spike rates per second) across the frontal and temporal lobes during a decision-making process.	5 years
Disruption of learning and memory via electrical stimulation (firing rates)	Measure the change in firing rates of neurons (measured in amplitude across frequency of the bandwidths) after applying small pulse of electrical activity during a learning task.	5 years
Disruption of learning and memory via electrical stimulation (memory)	Measure the change in memory (measured in spike rates per second) observed after applying small pulse of electrical activity during a learning task.	5 years

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Johns Hopkins University; University of Colorado, Denver; University Health Network, Toronto; National Institute of Neurological Disorders and Stroke (NINDS); Boston Children's Hospital; California Institute of Technology; University of California, Santa Barbara
• Investigators: Principal Investigator: Ueli Rutishauser, PhD, Cedars-Sinai Medical Center; Principal Investigator: Adam Mamelak, MD, Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2020
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: July 29, 2020
• First Submitted That Met QC Criteria: August 3, 2020
• First Posted (Actual): August 5, 2020

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 17, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Epilepsy; Memory; Decision-making; Depth Electrode
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Drug Resistant Epilepsy
• Other Study ID Numbers: STUDY00000572; 5U01NS117839-03 (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