Use of alpha-frequency deep transcranial interference stimulation (tIS) to understand and modify temporal dynamics of face emotion recognition and social/affective function.

A critical aspect of social cognition is the ability to infer emotion based upon facial expression, termed face emotion recognition (FER). We have recently shown that FER deficits in schizophrenia (Sz) and autism disorder spectrum (ASD) are associated with impaired activation and resting-state functional connectivity

within early visual regions and between early visual cortex and pulvinar nucleus (PuN) of the thalamus. Furthermore, we have shown that these deficits interrelate with impaired generation of alpha-frequency oscillations, which are known to mediate PuN-cortical connectivity. At present, tools for modulation of

oscillatory activity within deep structures are limited. In this project, we will implement a non-invasive deep brain stimulation technique termed transcranial Interference Stimulation (tIS) to directly modulate the oscillatory activity of PuN and to understand and modify temporal dynamics of FER and social/affective

function across healthy volunteers (HV) and Sz. tIS differs from more traditional transcranial electrical stimulation (tES) approaches such as transcranial alternating current stimulation (tACS) in that it uses two separate high-frequency (>1 kHz) carriers to introduce transcranial energy, and then create physiological-

range responses at the point where the two carriers intersect, corresponding to the beat frequency between them. Here, we will use carriers that differ by 8-12 Hz (depending on the individual's alpha frequency peak), permitting modulation of alpha-frequency interactions between PuN and visual cortex. The study will consist of

two specific aims. Under Aim 1, we will evaluate the effects of escalating tIS intensities and repeated dosing on dynamic pulvino-cortical interaction effects on face-emotion processes in HV using concurrent task-EEG recording and tIS, along with the target- and frequency-specificity of the effect. We will use a FER task in

which we previously reported visual sensory and FER differential patterns of PuN dysfunction and related oscillatory disturbance across Sz and ASD and task-related EEG modulations during tIS stimulation will be assessed. MRS read-outs will be used to assess tissue-level safety. Under Aim 2, we will conduct an RCT of

5d repeated tIS in Sz to assess its ability to correct ongoing deficits in alpha-frequency modulation during face processing, as well as its behavioral effects on FER. In accordance with the goals of the U01 mechanism, this project represents a collaborative partnership with Soterix Medical, Inc, which is developing tIS for clinical

use, serves as IDE sponsor and will provide the device and personalized, “exhaustive search” tIS field modeling routines for this project. The project will collect target-engagement, safety, tolerability and efficacy data needed to “de-risk” continued tIS development, while also evaluating critical mechanisms underlying

early visual processing and FER deficits in Sz. Novel features include personalized, fMRI-based native-space targeting, simultaneous tIS and EEG, and FDA IDE-approved MRS-based safety measures. If successful, this will permit future controlled studies to evaluate effects to ameliorate neuro- and social cognitive deficits across

neuropsychiatric disorders.