Modulating Oscillations and Working Memory in Patients With Subdural Electrodes

Purpose: To investigate whether rhythmic direct electrical stimulation (DES) causes entrainment of endogenous neural oscillatory activity and whether such activity improve cognition.

Participants: Drug-resistant epilepsy patients undergoing epilepsy surgery cortical mapping with continuous electrocorticography (ECoG) with intracranial electrodes.

Procedures (methods): Rhythmic electrical stimulation will be delivered via intracranial electrodes during routine extra-operative cortical mapping. Long-term ECoG, Pre-stimulation ECoG, peri-stimulation ECoG, and post-stimulation ECoG data will be analyzed to assess for entrainment of neural oscillations.

Study Overview

• Status: Enrolling by invitation
• Conditions: Epilepsy; Working Memory
• Intervention / Treatment: Device: Direct Cortical Stimulation Sham; Device: Direct Cortical Stimulation

Detailed Description

The aim of this study is to characterize the entrainment of endogenous neural oscillatory activity using direct electrical stimulation (DES) of the brain and understand the effects on cognition.

In this study, the investigators will apply rhythmic DES to patients who are undergoing routine DES for cortical mapping as a part of their epilepsy surgery evaluation with the aim of entraining cortical neural oscillations at specific frequencies relevant to cognitive processing and neuropsychiatric disease. The investigators hypothesize that rhythmic DES within a naturally occurring oscillatory frequency will cause entrainment at that frequency (e.g. 10Hz rhythmic DES will entrain a 10 Hz alpha oscillation). Also, the investigators posit that rhythmic DES at the theta (5Hz), alpha(10Hz), and gamma (50Hz) frequencies will cause enhancement of neural oscillations in the gamma band.

The study follows a within-participant crossover design. Participants will perform one of the tasks described below and each task consists of multiple trials of varying difficulty. Stimulation will be applied concurrently through electrodes implanted for clinical determination of seizure focus. Equal number of stimulation and sham trials will be pseudo-randomly interleaved to get a balanced design (balanced across trial difficulty and trial type).

The investigators will apply electrical stimulation in the form of pulse trains. The applied electrical stimulation intensity, duration and frequency follow the parameters used for clinical assessments of language and seizure focus and fall below the clinically approved limits.

The investigators will measure participants performance on a simple working memory task during the above-described cortical electrical stimulation protocol. Alternately, participants can perform a face recognition task.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. History of medically intractable epilepsy
2. Capable of giving informed consent
3. Aged 18 - 80 years, either sex

Exclusion Criteria:

1. Past or current history of other neurological illnesses including ischemic stroke, intracerebral hemorrhage, brain neoplasm.
2. Major systemic illness
3. Severe cognitive impairment defined as mini-mental state examination of less than 20
4. Severe psychiatric illness
5. Excessive use of alcohol or other substances

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham; Device: Direct Cortical Stimulation Sham. Trials in which stimulation is not applied. These trials are initiated using a generic trigger generator.	Device: Direct Cortical Stimulation Sham; Sham trials where no electric pulse is delivered
Active Comparator: Stimulation; Device: Direct Cortical Stimulation. 150 stimulations with stimulations lasting 5 seconds at different target electrodes at two target frequencies (e.g. 5 Hz and 10 Hz) 2 milliampere in amplitude (Pulse shape - Biphasic square pulse 200 microsecond in duration per phase). Stimulation will be applied concurrently with the task and stimulation trials will be randomly interleaved with sham trials.	Device: Direct Cortical Stimulation; A train of periodic electrical pulses is delivered between two local electrodes implanted in the brain

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Working Memory Task Performance - Accuracy	In this task, a sequence of items (alphabets or numerals) is presented followed by a delay. Following this, a single item which may or may not have been in the sequence is presented and the subject will be asked to indicate whether the item was in the previously presented sequence. A total of 150 trials will be performed with randomly interleaved sham trials where no stimulation is applied. Accuracy will be quantified in percentage correct.	1 Hour
Working Memory Task Performance - Reaction Time	In this task, a sequence of items (alphabets or numerals) is presented followed by a delay. Following this, a single item which may or may not have been in the sequence is presented and the subject will be asked to indicate whether the item was in the previously presented sequence. A total of 150 trials will be performed with randomly interleaved sham trials where no stimulation is applied. Reaction times will be quantified in milliseconds.	1 Hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial EEG	Spectral analysis and functional connectivity analysis of electrophysiology data will be performed using methods like multi-taper fft, wavelets, phase locking, Granger causality etc. The measures will be compared between sham and stimulation trials to identify if stimulation enhances neuronal entrainment. The correlation between the measures described above and the task performance will also be estimated.	Intracranial EEG will be collected simultaneously when the participants perform the task. 1 Hour

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Facial Recognition Task Performance - Accuracy	Participants who consent will be administered this task. On a given trial, participants will be presented with images of two faces side-by-side. The faces will either match in terms of emotion category (e.g., 2 anger faces) or not (e.g., an anger face and a fear face). Faces presented together will always be of the same gender but different identities. Participants will be asked to determine whether the two faces presented depict the same emotion category. Participants will have 5 seconds to make the decision and indicate by pressing a key in the keyboard. Accuracy will be quantified in percent correct.	1 Hour
Facial Recognition Task Performance - Reaction Time	Participants who consent will be administered this task. On a given trial, participants will be presented with images of two faces side-by-side. The faces will either match in terms of emotion category (e.g., 2 anger faces) or not (e.g., an anger face and a fear face). Faces presented together will always be of the same gender but different identities. Participants will be asked to determine whether the two faces presented depict the same emotion category. Participants will have 5 seconds to make the decision and indicate by pressing a key in the keyboard. Reaction times will be quantified in milliseconds.	1 Hour

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Mental Health (NIMH); National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Hae Won Shin, MD, University of North Carolina, Chapel Hill; Principal Investigator: Flavio Frohlich, PhD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Alagapan S, Schmidt SL, Lefebvre J, Hadar E, Shin HW, Frӧhlich F. Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent. PLoS Biol. 2016 Mar 29;14(3):e1002424. doi: 10.1371/journal.pbio.1002424. eCollection 2016 Mar.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: February 22, 2017
• First Submitted That Met QC Criteria: April 6, 2017
• First Posted (Actual): April 12, 2017

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Facial recognition
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy
• Other Study ID Numbers: 13-2710; 1R01MH124387 (U.S. NIH Grant/Contract); 1R21NS094988 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified electrophysiology data and task information (e.g. timing of each trial, timing of responses) will be shared at the end of the study in a central repository (e.g. zenodo)

Study Data/Documents

1. Summary Data Set
   Information comments: Dataset supporting Alagapan et al. 2016 PLoS Biology