# Changing the neuromodulation game: ultrasound fenestration of the blood brain barrier for noninvasive viral transfection of primate CNS neurons

> **NIH NIH R34** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $752,571

## Abstract

Summary
Genetic technologies have revolutionized the way scientists can dissect out brain circuitry by inserting G
protein-coupled receptors that enable selective modulation of neurons in target structures. Amongst them,
 a promising tool,DREADDS (designer receptors exclusively activated by designer drugs) is used to modulate
neural activity pharmacologically in targeted brain regions. Unfortunately, DREADDS also require invasive
methods to deliver the genes that express the receptor. Focused Ultrasound (FUS) is a novel approach that
focuses an ultrasound beam through the skull and meninges to reach deep brain structures and directly
stimulate or inhibit neurons in the targeted region. Combined with lipid microbubbles, focused ultrasound can
be used to open the blood-brain barrier (BBB) in targeted brain regions. This method is non-invasive, but
spatially precise. Focused ultrasound mediated BBB opening has been used to deliver optogenetic viruses in
rodent models. Here, we propose to test if this approach can be used to express DREADDS in targeted brain
regions in nonhuman primates (rhesus monkeys). We will open the BBB using FUS with microbubbles. The
BBB remains open for 24 to 48 hours. During this time, a viral delivery system will be used to introduce
DREADDS by intravenous injection. The DREADDS should circulate through the bloodstream and enter the
brain only in the region where the BBB has been opened. This entire procedure is completely noninvasive.
We will test the functional effects of DREADDS using a fMRI and electrophysiology. We will then confirm
DREADD expression using post-mortem histology. The development of FUS-based DREADD delivery could
make deep brain neuromodulation available for patients who are not candidates for surgical approaches. The
proposed experiments are essential for establishing the efficacy of focused ultrasound mediated DREADD
delivery to treat psychiatric illnesses that affect cognition and motivation. FUS-based chemogenetic therapy
could become a non-surgical alternative for patients with psychiatric disorders who would benefit from DBS

## Key facts

- **NIH application ID:** 10235811
- **Project number:** 1R34NS122272-01
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** Arnaud Y Falchier
- **Activity code:** R34 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $752,571
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235811

## Citation

> US National Institutes of Health, RePORTER application 10235811, Changing the neuromodulation game: ultrasound fenestration of the blood brain barrier for noninvasive viral transfection of primate CNS neurons (1R34NS122272-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10235811. Licensed CC0.

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