Using Direct Brain Stimulation to Study Cognitive Electrophysiology

National Institute of Neurological Disorders and Stroke (NINDS), Emory University, Thomas Jefferson University, University of Texas Southwestern Medical Center, The University of Texas Health Science Center at San Antonio, University of Colorado, Denver

This project forms a multi-site research collaboration to carry out verbal and spatial memory experiments in patient volunteers to better understand the neural bases of human memory, employing direct electrical brain stimulation as a tool to study those dynamics and their relationship to memory performance.

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.

Stimulation will be applied concurrently with the task, if applicable, and stimulation trials will be interleaved with sham trials, where no stimulation is delivered.

Stimulation lasting from 500 to 2000 milliseconds on bipolar target electrode pairs at one of two target frequencies (e.g. 10 Hz and 200 Hz), up to 1.5 milliamperes in amplitude on depth contacts and 3.5 milliamperes in amplitude on surface contacts. (Pulse shape - Charge-balanced biphasic rectangular pulses with pulse width of 300 microseconds in duration per phase).

To measure memory performance, participants will perform a custom episodic memory task (verbal, spatial), with performance compared between sham and stimulation trials to identify if stimulation modulates memory. The primary outcome measure is memory performance, such as the percentage of recalled items.

Intracranial electrophysiological recordings: Intracranial Electroencephalogram (iEEG), Spectral Power

Spectral power will be compared between sham and stimulation trials to identify whether stimulation modulates neuronal biomarkers of memory. Spectral power is measured in microvolts squared.

Phase and power based synchrony of iEEG data (across or within electrodes) will be compared between sham and stimulation trials to identify whether stimulation modulates neuronal biomarkers of memory. Synchrony can be measured as the length of a resultant vector in complex space and the correlation [-1 to 1] between two time series.

Analysis of unit activity data collected on microwire electrodes will be performed, with firing rates compared between sham and stimulation trials to identify if stimulation modulates the inhibitory-excitatory balance as reflected by decreased or increased firing rates. Firing rate is measured in Hz.

Synchrony of spike trains collected on microwire electrodes will be compared between sham and stimulation trials to identify if stimulation modulates neuronal biomarkers of memory. Synchrony will be measured between different neurons and with the phase of the ongoing local field potential. Synchrony can be measured as the length of a resultant vector in complex space and as the correlation [-1 to 1] between two time series.

Inclusion Criteria: Subjects will be enrolled who are expected to undergo intracranial electroencephalographic monitoring as part of a standard clinical procedure for the treatment of pharmacologically resistant epilepsy. Exclusion Criteria: The following individuals will be excluded: Any cognitive impairments that would limit their ability to participate in the memory testing, Any physical disability that would limit their ability to perform cognitive tasks within normal limits, Any psychiatric condition that would limit their ability to provide informed consent or to perform cognitive tasks within normal limits, Any medical condition that would, in the investigator's opinion, limit the subject's participation in the study, Who are pregnant, Unable or unwilling to provide informed consent.

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.

Study data will become available within six months of publication of the relevant results, with no planned expiration.