Subcortical Arousal in Perceptual Awareness

Shared Subcortical Arousal Systems Across Perceptual Modalities

The study consists of prospective enrollment of healthy participants and patients with epilepsy, as well as analysis of an existing data set. Healthy participants will be studied with fMRI, eye metrics and behavioral testing at Yale. Patients will be studied with thalamic recording and stimulation, eye metrics and behavioral testing.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy
• Intervention / Treatment: Device: EEG; Device: Eye Tracking; Device: Behavioral task; Diagnostic test: fMRI

Detailed Description

The goal of the planned studies is to investigate the role of shared subcortical arousal systems in perception, including visual, auditory and tactile perception. We will investigate shared subcortical arousal circuits in perception using techniques with complementary strengths including fMRI, pupil and eye gaze measurements, behavioral testing, and direct recording and stimulation of the thalamus.

Aims 1 and 2 will investigate subcortical arousal systems in visual, auditory and tactile perception using fMRI, pupil and eye gaze measurements and behavioral testing in healthy normal adult participants. We will collect data from participants for auditory (N=65) and tactile (N=65) perception, and will use an existing data set previously collected and published by our group for visual perception (N=65). For Aim 1 we will analyze fMRI changes in subcortical arousal areas comparing perceived vs not perceived stimuli, and will perform conjunction and disjunction analyses to combine results across visual, auditory and tactile tasks. For Aim 2 we will repeat this analysis but using report-independent perception data based on machine learning classification of eye metrics. Sample size estimates are based on our recent fMRI studies of visual perception which obtained robust statistically significant results in subcortical arousal areas with sample size of 65 participants (Kronemer et al., 2022). Testing is replicated in each participant on two different scanning days, counterbalanced across task-relevant stimulus type on each day. Data for the Visual Report + No Report perception task have already been collected and are publicly available through nitrc.org. Therefore, to obtain comparable data sets for auditory and tactile perception for Aims 1 and 2, we will recruit an additional 65 + 65 = 130 participants, each studied on two days of testing with Report + No Report Paradigms.

Aim 3 will investigate the role of the thalamic intralaminar region in visual perception using direct recording and stimulation from patients with chronically implanted thalamic electrodes previously placed for treatment of epilepsy. We will collect data from 32 patients for thalamic recordings only (Aim 3A) and from 16 patients for both thalamic recording and stimulation (Aim 3B). For Aim 3A we will analyze thalamic event related potentials in perceived vs not perceived stimuli, classified as in Aim 2 based on eye metrics. For Aim 3B, we will analyze the probability of perception for visual stimuli presented under three different conditions: thalamic stimulation simultaneous with the visual stimulus, thalamic stimulation delayed until 2s after the visual stimulus, and no thalamic stimulation. Sample size calculations for Aim 3A begin with our prior significant results with N=65 for scalp EEG in the Report + No Report Paradigm. Because we saw robust ERPs with N=7 in the thalamus using the Report Paradigm (Kronemer et al., 2022), as a reasonable conservative intermediate sample size for Report + No Report thalamic icEEG we will plan N=32, leveraging recruitment across multiple planned sites to achieve this number. For Aim 3B, preliminary data with thalamic stimulation show a mean effect size of ~20% ± 20% on probability of perception. Therefore, with 80% power and two-sided significance of p<0.05, we will require N=16 participants as a conservative estimate of sample size.

Human subjects research for Aims 1 and 2 will be performed at Yale University School of Medicine. For Aim 3, the study subject population will consist of epilepsy patients with electrodes previously implanted in the intralaminar thalamus (surgical implants are not part of the present study). Aim 3A will include patients with thalamic recording, eye metric, scalp EEG and behavioral measurements (N=32). Aim 3B will include patients with thalamic recording, thalamic stimulation, scalp EEG and behavioral measurements (N=16). Due to the special patient population planned for Aim 3, data will be collected at multiple sites (up to 11). This will be done by visits from Yale research personnel to each site, in collaboration with local site investigators. Site investigators will identify epilepsy patient participants with chronically implanted thalamic intralaminar electrodes to be recruited for the research.

• Study Type: Interventional
• Enrollment (Estimated): 202
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hal Blumenfeld, MD, PHD; Phone Number: (203) 785-3865; Email: Hal.blumenfeld@yale.edu
• Study Contact Backup: Name: Kristine Dacosta; Email: kristine.dacosta@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale School of Medicine
      • Principal Investigator: Hal Blumenfeld, MD, PhD
      • Sub-Investigator: Imran Quraishi, MD, PhD
      • Contact: Francois Stockart; Email: francois.stockart@yale.edu
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Recruiting
      • University of Kansas Medical Center
      • Contact: Laura Crabtree; Email: lcrabtree2@kumc.edu
      • Principal Investigator: Utku Uysal, MD, MS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Erin Kaye Donahue, PhD; Email: ekdonahue@mgh.harvard.edu
      • Principal Investigator: Mark Richardson, MD, PhD
      • Sub-Investigator: Peter Hadar, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55901
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Jamie Van Gompel, MD
      • Contact: Ana Sanchez; Email: sanchez.ana2@mayo.edu
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Not yet recruiting
      • Dartmouth Hitchcock Medical Center
      • Principal Investigator: Barbara Jobst, MD
      • Contact: Anastasia Kanishcheva, MPH; Email: anastasia.kanishcheva@hitchcock.org
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • Not yet recruiting
      • University of Pittsburgh Medical Center
      • Contact: Dane Prince; Email: dep137@pitt.edu
      • Principal Investigator: Alexandra Urban, MD
  • Tennessee
    • Nashville, Tennessee, United States, 37235
      • Recruiting
      • Vanderbilt University Medical Center
      • Principal Investigator: Dario Englot, MD, PhD
      • Contact: Kate Wang; Email: kate.wang.1@vumc.org
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine
      • Principal Investigator: Sameer Anil Sheth, MD, PhD
      • Contact: Victoria Gates; Email: victoria.gates@bcm.edu
      • Sub-Investigator: Vaishnav Krishnan, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

A. The following are the inclusion/exclusion criteria for healthy participants age 18 years and up (Aim 1 and 2):

Inclusion: (1) normal vision with or without the use of corrective lenses; (2) normal hearing not needing an assistive hearing device.

Exclusion: (1) past history of diagnosis of a psychiatric or neurologic disease; (2) current psychiatric or neurologic disease; (3) requires hard contact lenses or glasses to maintain normal vision (prevents accurate pupil and eye gaze measurements); (4) pregnant or nonremovable ferrous metal objects inside or on the body (prevents MRI).

B. The following are the inclusion/exclusion criteria for epilepsy patients with thalamic electrodes age 13 years and up (Aim 3A):

Inclusion: (1) normal vision with or without the use of corrective lenses; (2) normal hearing not needing an assistive hearing device.

Exclusion: (1) requires hard contact lenses or glasses to maintain normal vision (prevents accurate pupil and eye gaze measurements); (2) unable to perform the perception task due to cognitive impairment

C. The following are the inclusion/exclusion criteria for epilepsy patients with thalamic electrodes age 18 year and up (Aim 3B):

Inclusion: (1) normal vision with or without the use of corrective lenses; (2) normal hearing not needing an assistive hearing device.

Exclusion: (1) unable to perform the perception task due to cognitive impairment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thalamic Recording (Aim 3A); Participants will perform the visual behavioral task with intracranial electroencephalogram (EEG) brain recordings carried out in parallel with surface EEG recordings. For Aim 3A, we will analyze thalamic event related potentials in perceived vs not perceived stimuli, classified as in perception of no report visual stimuli based on eye metrics.	Device: EEG; Participants will have scalp EEG recorded with the international 10-20 system sampled at 256Hz using EEG amplifiers for purposes of surface event related potential analysis; Device: Eye Tracking; An eye-tracking device may be used during the perceptual awareness task. Pupillary and gaze location measurements are recorded using either a ViewPoint~VoltagePro.EyeLink 1000 Plus system, or Argus Science ETVision system. If using the ViewPoint~VoltagePro system or the Argus Science ETVision system, participants will be asked to wear an eye tracker during the perceptual awareness task (similar to wearing sunglasses). If using the EyeLink 1000 Plus system, participants may be asked to place their head inside of a padded head-chin rest to stabilize head position; Device: Behavioral task; For the visual perceptual awareness task, the participant will be presented with barely perceptible visual stimuli. After a variable delay, the participant will be asked to report perception of each stimulus and identify its location.
Experimental: Thalamic Stimulation (Aim 3B); We will test participants during the Visual Report Paradigm, while recording from the intralaminar thalamus with simultaneous scalp EEG as in Aim 3A. Three thalamic stimulation conditions will be tested, randomized across trials: 1. No stimulation; 2. Stimulation Concurrent with visual stimuli; 3. Stimulation Delayed to 2s after visual stimuli. Stimulation will be a 100Hz train lasting 300ms, with biphasic square wave pulses 120μs per phase, current adjusted previously by clinicians to maximum tolerated level without side effects (typically ~3mA). The electrical stimulation is being delivered for research purposes to understand the causal role of thalamus in regulating visual perception.	Device: EEG; Participants will have scalp EEG recorded with the international 10-20 system sampled at 256Hz using EEG amplifiers for purposes of surface event related potential analysis; Device: Eye Tracking; An eye-tracking device may be used during the perceptual awareness task. Pupillary and gaze location measurements are recorded using either a ViewPoint~VoltagePro.EyeLink 1000 Plus system, or Argus Science ETVision system. If using the ViewPoint~VoltagePro system or the Argus Science ETVision system, participants will be asked to wear an eye tracker during the perceptual awareness task (similar to wearing sunglasses). If using the EyeLink 1000 Plus system, participants may be asked to place their head inside of a padded head-chin rest to stabilize head position; Device: Behavioral task; For the visual perceptual awareness task, the participant will be presented with barely perceptible visual stimuli. After a variable delay, the participant will be asked to report perception of each stimulus and identify its location.
Experimental: fMRI with report + no-report perception paradigms (Aims 1 and 2); Participants will consist of healthy adults undergoing fMRI, eye metric and behavioral testing with report + no-report perception paradigms. This will include prospective data collection for the auditory paradigm, tactile paradigm, as well as analysis of an existing data set for the visual paradigm.	Device: EEG; Participants will have scalp EEG recorded with the international 10-20 system sampled at 256Hz using EEG amplifiers for purposes of surface event related potential analysis; Device: Eye Tracking; An eye-tracking device may be used during the perceptual awareness task. Pupillary and gaze location measurements are recorded using either a ViewPoint~VoltagePro.EyeLink 1000 Plus system, or Argus Science ETVision system. If using the ViewPoint~VoltagePro system or the Argus Science ETVision system, participants will be asked to wear an eye tracker during the perceptual awareness task (similar to wearing sunglasses). If using the EyeLink 1000 Plus system, participants may be asked to place their head inside of a padded head-chin rest to stabilize head position; Device: Behavioral task; For the visual perceptual awareness task, the participant will be presented with barely perceptible visual stimuli. After a variable delay, the participant will be asked to report perception of each stimulus and identify its location.; Diagnostic test: fMRI; Visual, auditory or tactile behavioral task will be performed during fMRI at the Yale MR Center. The subject will be asked to lie still in a 3T magnet scanner for up to 15-minute blocks. Each subject will have a sagittal T1-weighted localizer scan (3 minutes) and axial-oblique T1-weighted images (3 min). Multiple 5-15-minute imaging runs will be repeated up to 10 times. The subjects' responses will be recorded by a computer that is linked to the button box. The stimuli will be presented in blocks of 5 to 15 minutes throughout the MR imaging sequences.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subcortical event-related signals	Subcortical event-related signals will be recorded by icEEG to assess electrical activity from the cerebral cortex using currently implanted electrodes during the behavioral task	Immediately after the intervention
Perceptual Sensitivity	measured by the percentage of correctly perceived trials for each participant (Aim 3B)	Immediately after the intervention
Activity changes	Measured using functional magnetic resonance imaging (fMRI) during task onset and off-set to fixation and compare them to fMRI changes during conscious perception of a stimulus vs. not-reported stimuli (Aims 1 and 2)	Immediately after the intervention
Functional connectivity	Measured using fMRI to establish networks actively engaged during task vs. fixation and consciously-reported vs. not-reported stimuli (Aims 1 and 2).	Immediately after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical Event Related Potentials	Cortical event related potentials will be measured by scalp EEG to assess brain wave changes at the surface level during the perceptual awareness task	Immediately after the intervention

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Hal Blumenfeld, MD, Phd, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2025
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: March 19, 2025
• First Submitted That Met QC Criteria: April 10, 2025
• First Posted (Actual): April 18, 2025

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Diagnostic Techniques and Procedures; Diagnosis; Tomography; Diagnostic Imaging; Diagnostic Techniques, Neurological; Electrodiagnosis; Eye Movement Measurements; Diagnostic Techniques, Ophthalmological; Magnetic Resonance Imaging; Electroencephalography; Eye-Tracking Technology
• Other Study ID Numbers: 2000037710; 1R01NS134655-01A1 (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: Yes
• product manufactured in and exported from the U.S.: Yes