Subcortical Arousal in Perceptual Awareness

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 or acutely implanted thalamic electrodes previously placed for treatment of epilepsy. We will collect data from 32 patients for intracranial thalamic or cortical 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 implanted in the intralaminar thalamus for clinical reasons (surgical implants are not part of the research study). Aim 3A will include patients with intracranial thalamic and cortical 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 or acutely implanted thalamic intralaminar electrodes to be recruited for the research.

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

Exclusion: (1) severe vision impairment even with correction preventing ability to see stimuli (prevents accurate pupil and eye gaze measurements); (2) unable to perform the perception task due to cognitive impairment. All participants must be capable of consenting for themselves.

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) A female subject must have a negative pregnancy test and if sexually active, must be using a reliable form of birth control for the duration of the trial, be surgically sterile, or be at least two years post-menopausal.

Exclusion: (1) severe vision impairment even with correction preventing ability to see stimuli (prevents accurate pupil and eye gaze measurements); (2) unable to perform the perception task due to cognitive impairment. All participants must be capable of consenting for themselves; (3) Pregnancy.