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Next generation transcranial ultrasound-based neuromodulation using phase shift nanoemulsions

Award Number: R01MH132022
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027
AWARD TERMINATION DATE: 04/24/2025

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Next generation transcranial ultrasound-based neuromodulation using phase shift nanoemulsions - Project Summary This proposal responds to PAR-22-039 and aims to develop focused ultrasound (FUS) as a next generation high precision device-based pharmacological neuromodulation tool and evaluate its use in non- human primates as a translational step to humans. Current device-based neuromodulation technologies rely on interaction with cells’ endogenous sensitivities to different forms of energy. Although FUS alone overcomes spatial and depth limitations of other non-invasive neuromodulation modalities, the diverse response of cells to FUS presents a limitation and can make predictable neuromodulation difficult. We seek to move beyond the paradigm of modulating via endogenous sensitivity by developing FUS in combination with phase shift nanoemulsions (PSNEs)—200 nm liquid particles that can carry a drug payload and become microbubbles when exposed to brief (<1 msec) FUS pulses above a threshold. By developing FUS combined with PSNEs, we will be able to predictably modulate millimeter-scale regions throughout the brain by either locally enhancing blood brain barrier (BBB) permeability and injecting a drug or by releasing drugs from PSNEs loaded with a drug. We propose a research plan that will move these technologies forward in the non-human primate as an important translational step to humans. We first propose to develop an ultrasound transducer that will decrease the focal spot size including receive elements that will allow us to map particle activation through the skull. We will integrate the transducer into a FUS neuromodulation system built by our team under the BRAIN Initiative and develop open-source software that will improve treatment planning for FUS neuromodulation. We will apply this system to open the BBB in the sensorimotor region by activating PSNEs, driving the resultant microbubble and injecting the inhibitory drug GABA, which does not cross the unopened BBB in concentrations high enough to inhibit neurons. Because opening the BBB is not desirable in many scenarios, we will also develop activatable drug-loaded PSNEs to locally deliver the anesthetic sodium pentobarbital without opening the BBB. We will characterize the inhibitory effect of both neuromodulation methods using BOLD fMRI and assess safety using neuroimaging and behavioral analysis. Our multidisciplinary team has all expertise for MR-guided FUS with fMRI feedback and will collaborate with co- investigator Dayton whose laboratory developed a condensation-based PSNE formulation that uses the same excipients as commercially approved contrast agents. The acoustic technologies we propose to develop would improve the spatial capabilities of FUS neuromodulation and explore two approaches for focal pharmacological neuromodulation in the monkey including safety assessments that pave the way for translation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $765,144 )
2026	2026	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	4	2/10/2026	NON-COMPETING CONTINUATION	$765,144
														Subtotal = $765,144

Issue Date FY: 2025 ( Subtotal = $854,231 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	3	12/19/2024	NON-COMPETING CONTINUATION	$659,268
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	3	12/20/2024	SUPPLEMENT FOR EXPANSION	$78,621
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	002	3	4/23/2025	NON-COMPETING CONTINUATION	$0
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	003	3	4/24/2025	TERMINATION	$0
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	004	3	6/10/2025	NON-COMPETING CONTINUATION	$116,342
														Subtotal = $854,231

Issue Date FY: 2024 ( Subtotal = $838,910 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	2	1/4/2024	NON-COMPETING CONTINUATION	$701,304
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	002	2	7/9/2024	NON-COMPETING CONTINUATION	$77,923
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	2	6/11/2024	SUPPLEMENT FOR EXPANSION	$59,683
														Subtotal = $838,910

Issue Date FY: 2023 ( Subtotal = $812,393 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	1	1/31/2023	NEW	$812,393
														Subtotal = $812,393

Grand Total All Awards = $3,270,678

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Next generation transcranial ultrasound-based neuromodulation using phase shift nanoemulsions

Award Number: R01MH132022

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

AWARD TERMINATION DATE: 04/24/2025

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