Memory Retrieval and Encoding Investigated by Neural Stimulation (MEMREINS)

The purpose of this research is to understand biomarkers of human memory through correlational analyses and to use focal electrical stimulation as a causal manipulation to understand how biomarkers of memory relate to other brain states and behavioral measures.

Study Overview

• Status: Active, not recruiting
• Conditions: Epilepsy Intractable
• Intervention / Treatment: Device: Direct electrical stimulation

Detailed Description

The study protocol outlines fundamental experiments to understand the neural dynamics underlying human memory and use direct brain stimulation as a tool (intervention) to study the relationship between those dynamics and memory performance. The investigators will collect recording and stimulation data from 250 patient volunteers as they perform carefully-matched verbal and spatial memory tasks. During non-stimulation sessions, the investigators will measure correlative neural biomarkers of memory encoding and retrieval using standard clinical depth electrodes and micro-wire recordings. To test the causal role of these biomarkers, the investigators will employ direct brain stimulation to briefly modulate neural activity, and measure ensuing changes in behavioral performance. With a set of causal biomarkers and predictive models in hand, the investigators will finally ask whether model-driven stimulation paradigms offer the investigators the ability to reliably modulate neural activity, and consequent behavior, in real-time.

• Study Type: Interventional
• Enrollment (Estimated): 800
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado, Denver
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institute of Neurological Disorders and Stroke
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03766
      • Dartmouth-Hitchcock Medical Center
  • New York
    • New York, New York, United States, 10027
      • Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Expected to undergo intracranial implantation and postoperative electroencephalographic monitoring as part of a standard clinical procedure for the treatment of pharmacologically resistant epilepsy
2. Age 18 or older

Exclusion Criteria:

1. Any physical or cognitive disability or illness that would limit their ability to perform cognitive tasks
2. Any medical condition that would, in the investigator's opinion, limit the subject's participation in the study.
3. Unable or unwilling to provide informed consent
4. MRI contraindications

Standard clinical care includes a pregnancy test for female patients prior to the surgical implantation of the electrodes. Pregnant women are not surgically implanted.

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: Direct Electrical Stimulation; Stimulation will be applied concurrently with the task, if applicable, and stimulation trials will be interleaved with sham trials, where no stimulation is delivered.	Device: Direct electrical stimulation; Stimulation will not exceed 0.75 mA and will be approved prior by study investigators. Each subject will have a safety threshold testing at the beginning of each session and if 'afterdischarges' occur the subject's stimulation threshold will be lowered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To use direct electrical stimulation to disentangle causal versus correlative biomarkers of verbal and spatial episodic memory	1. We will use linear mixed effects models and L2-penalized logistic regression classifiers to compare periods of successful and unsuccessful performance in our tasks	Up to 4 weeks (typical duration of hospital stay)
To develop and test models of human brain dynamics in the presence of electrical stimulation	2. We will compare spectral indices of brain activity before and after stimulation as a function of stimulation parameters.	Up to 4 weeks (typical duration of hospital stay)
To assess how reactivation of prior memories shapes subsequent recall and memory organization, including memory for the content, context and value of experiences.	3. We will mathematical models of neural similarity described in detail in Halpern (2024) and Manning (2011, 2012) to test the reactivation mechanisms described in Lohnas et al. (2014) and Healey and Kahana (2015).	Up to 4 weeks (typical duration of hospital stay)
To determine whether state-dependent stimulation can separately be used to modulate encoding and retrieval processes	4. We will evaluate the closed-loop stimulation protocol described in Kahana et al. (2023) in both encoding and retrieval.	Up to 4 weeks (typical duration of hospital stay)
To determine whether stimulation is more effective at modulating memory when targeted to regions with specific connectivity profiles to the medial temporal lobe	5. We will compare recall rates during a free recall experiment with brain stimulation at sites with high network-mediated activation, as described in Solomon et al. (2018), versus low network-mediated activation.	Up to 4 weeks (typical duration of hospital stay)
To determine how simultaneous stimulation at multiple target sites can be optimized to modulate memory	6. We will compare recall rates during a free recall experiment with no brain stimulation, stimulation at one site, and stimulation at multiple sites.	Up to 4 weeks (typical duration of hospital stay)

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Columbia University; National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Michael Kahana, PhD, University of Pennsylvania

Publications and helpful links

General Publications

• Ezzyat Y, Kragel JE, Solomon EA, Lega BC, Aronson JP, Jobst BC, Gross RE, Sperling MR, Worrell GA, Sheth SA, Wanda PA, Rizzuto DS, Kahana MJ. Functional and anatomical connectivity predict brain stimulation's mnemonic effects. bioRxiv [Preprint]. 2023 Aug 11:2023.07.27.550851. doi: 10.1101/2023.07.27.550851.
• Ezzyat Y, Wanda PA, Levy DF, Kadel A, Aka A, Pedisich I, Sperling MR, Sharan AD, Lega BC, Burks A, Gross RE, Inman CS, Jobst BC, Gorenstein MA, Davis KA, Worrell GA, Kucewicz MT, Stein JM, Gorniak R, Das SR, Rizzuto DS, Kahana MJ. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018 Feb 6;9(1):365. doi: 10.1038/s41467-017-02753-0.
• Kragel JE, Ezzyat Y, Lega BC, Sperling MR, Worrell GA, Gross RE, Jobst BC, Sheth SA, Zaghloul KA, Stein JM, Kahana MJ. Distinct cortical systems reinstate the content and context of episodic memories. Nat Commun. 2021 Jul 21;12(1):4444. doi: 10.1038/s41467-021-24393-1.

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2014
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 24, 2020
• First Submitted That Met QC Criteria: February 24, 2020
• First Posted (Actual): February 27, 2020

Study Record Updates

• Last Update Posted (Estimated): November 5, 2024
• Last Update Submitted That Met QC Criteria: November 4, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: episodic memory
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Drug Resistant Epilepsy
• Other Study ID Numbers: 820553; 1U01NS113198-01 (U.S. NIH Grant/Contract); 5R01NS106611-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be shared in a public repository at regular intervals during the project. De-identified data sets will be anonymized prior to posting on the public repository. These de-identified data are likely to be analyzed for secondary purposes other than those described in this protocol (e.g. seizure prediction). Shared data will include, at a minimum, digital spreadsheets used to summarize all participant behavioral data. De-identified electrophysiology data, demographic information, electrode localization information, and task information (e.g. timing of each trial, timing of responses) will be shared in a central repository. Descriptions of the tasks and stimuli will be shared. De-identified references to individual participant data may also appear in scientific journal publications or presented at scientific meetings.
• IPD Sharing Time Frame: Study data will become available within six months of publication of the relevant results, with no planned expiration.
• IPD Sharing Access Criteria: Data is freely available, will require a formal request for access.

Drug and device information, study documents

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