# Advancing non-invasive brain stimulation: A CompreheNSive Study of Temporal Interference Mechanisms (CNS-STIM)

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $378,453

## Abstract

PROJECT SUMMARY/ABSTRACT
Temporal Interference (TI) is an innovative non-invasive brain stimulation technique that holds great promise. It
utilizes high-frequency electrical currents (e.g., 1000 Hz and 1000 + Δf Hz) to achieve deep and precise brain
stimulation. TI is characterized by the simultaneous application of two high-frequency electrical signals, each
with a specific offset frequency (referred to as Δf). This combination results in the creation of an amplitude
modulation (AM), at depth, considered to be the stimulating signal within the targeted brain structure. However,
despite its theoretical potential and successful application in the peripheral nervous system, there are significant
gaps in our understanding of how TI truly functions within the central nervous system (CNS). To bridge this
knowledge gap, this three-year research project is structured around three specific aims. Aim 1 delves into the
spatial precision, focality, and depth of TI stimulation. We will examine the correlation between the size of AM
and its impact on neuronal activation using real-time calcium level monitoring in brain slices, finite element
simulations, recording in anesthetized mice and expression of immediate early genes (IEGs - i.e., c-fos, c-jun,
arc). Aim 2 explores the frequency of AM (Δf) generated by TI and its potential interaction with carrier
frequencies. We will use genetically encoded voltage indicators to study cellular dynamics (cell type specific
response to TI stimulation i.e., glutamatergic, GABAergic) in brain slices on a microelectrode array. We will also
examine the impact of varying Δf in vivo with the co-localization of neuronal subtype (glutamatergic vs GABAergic
cells) and IEGs. Aim 3 investigates the differential effects of TI on neurons and fibers within the CNS. We will
grow primary neurons in microfluidic chambers to physically separate cell bodies from axons and compare soma
versus axon targeted by TI in vitro. Additionally, by varying the orientation of electrode pairs in vivo, we will also
compare direct TI stimulation of specific nuclei (i.e., septum and hippocampus) versus stimulation of the
pathways (i.e., septo-hippocampal and perforant). Finally, we will combine TI with reversible chemogenetic
neuromodulation to reveal if TI stimulation is enhanced when targeting the pathways projecting to the specific
target structure, as opposed to directly stimulating the target itself. Through this multifaceted research, we aim
to bridge the gap between TI's theoretical promise and its practical applications, ultimately advancing our
understanding of non-invasive neuromodulation and its potential clinical implications.

## Key facts

- **NIH application ID:** 10946265
- **Project number:** 1R01NS138733-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ken Berglund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,453
- **Award type:** 1
- **Project period:** 2024-08-14 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946265

## Citation

> US National Institutes of Health, RePORTER application 10946265, Advancing non-invasive brain stimulation: A CompreheNSive Study of Temporal Interference Mechanisms (CNS-STIM) (1R01NS138733-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10946265. Licensed CC0.

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