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Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine

Award Number: R00HD101702
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine - PROJECT SUMMARY The goals of this study are to target the neurobiology underlying restricted and repetitive behaviors (RRB) in children with autism spectrum disorder (ASD) using N-acetylcysteine (NAC), a well-tolerated nutritional supplement and glutamatergic modulator that has exhibited efficacy for reducing RRB severity in recent preliminary trials. The goals of this career developmental award are to learn the theoretical principles and develop practical application techniques for proton spectroscopy (1H MRS) and electroencephalography (EEG) approaches in children with neurodevelopmental disorders, learn clinical trial methodologies and develop skills for examining treatment efficacy in controlled trials, and learn advanced statistical modeling techniques for assessing complex treatment-related outcomes in pediatric populations. The ultimate overarching goal is to support a promising early career investigator in transitioning to an independent research position. To achieve these goals, we will (Aim 1) acquire 1H MRS and EEG data from children with ASD who exhibit severe RRB and examine the ability of NAC to modulate excitatory signaling in cortico-striatal circuits (CSC) in a single dose challenge study (NAC and placebo). We will also (Aim 2) examine the efficacy of NAC for improving RRB in a 12-week randomized controlled trial and (Aim 3) assess the ability of neurobiological measures of excitatory signaling (1H MRS and EEG) to predict treatment response. CSC are a salient treatment target because CSC contribute to RRB in mouse models of ASD and exhibit relationships with RRB severity in children with ASD. Altered excitatory signaling in CSC regions have also been reported in children/adults with ASD, and most importantly, NAC can modulate glutamatergic signaling in CSC regions. Thus, excitatory (i.e. glutamatergic) signaling in CSC in ASD may contribute to the severity of RRB, at least for some individuals, and modulation with NAC may confer some clinical benefits, especially for children with elevated levels at baseline. We expect that children with ASD who receive NAC will exhibit a larger reduction in 1H MRS and EEG measures of glutamatergic signaling compared to children who receive placebo, which will be associated with a larger reduction in RRB severity following 12 weeks of treatment with NAC compared to placebo. We expect that baseline measures will also be able to accurately predict which children respond to NAC and will explore the effects of NAC on different subtypes of RRB, which may be due to different neurobiological alterations. The findings from this research will support the efficacy of NAC for the treatment of RRB and shed light on the mechanisms of action underlying NAC-mediated improvements. This is particularly important because there are currently no drug treatments for the core symptoms of ASD, including RRB, and severe RRB are associated with management challenges and barriers to adaptive learning. With this training, I plan to develop a programmatic line of research to identify the neurobiology of specific symptoms in children with ASD and develop objective biological markers that can be used to improve treatment-related research and help advance precision medicine.


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: 2025 ( Subtotal = $248,999 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	5	1/22/2025	NON-COMPETING CONTINUATION	$224,100
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	5	4/16/2025	NON-COMPETING CONTINUATION	$24,899
														Subtotal = $248,999

Issue Date FY: 2024 ( Subtotal = $246,620 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	002	4	4/30/2024	NON-COMPETING CONTINUATION	$22,410
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	4	1/22/2024	NON-COMPETING CONTINUATION	$224,099
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	3	12/11/2023	EXTENSION WITH OR WITHOUT FUNDS	$111
														Subtotal = $246,620

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	3	1/30/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $744,619

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Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine

Award Number: R00HD101702

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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