Wednesday, January 15, 2025 1/15/2025

Multiscale models of proprioceptive encoding to reveal mechanisms of impaired sensorimotor control

Award Number: R01HD090642
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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PROJECT SUMMARY Our long-term goal is to identify neural mechanisms and the functional roles of sensorimotor signals in health and disease as needed to guide mechanistically targeted diagnoses, assessments, and treatments for neurological movement disorders. Here we address the scientific barriers to understanding and treating a broad class of movement disorder symptoms recently defined as joint hyper-resistance, which encompass spasticity in stroke, spinal cord injury, or cerebral palsy; parkinsonian rigidity, and hypertonia. The objective of this collaborative, interdisciplinary proposal is to identify neural mechanisms of hyper-resistance and dissociate their relative roles in abnormal movement. We will focus on the neural mechanisms underlying two clinically- defined neural contributions to hyper-resistance: non-velocity dependent involuntary background activation and velocity-dependent stretch hyper-reflexia. We hypothesize that increased spinal excitability in many neurological disorders causes involuntary background activation and velocity-dependent stretch hyper-reflexia via three dissociable neural mechanisms: 1) alpha-drive to extrafusal muscle fibers increasing background muscle tension, 2) gamma-drive to specialized intrafusal muscle fibers in muscle spindles sensory organs, increasing their sensitivity to muscle stretch, and 3) sensorimotor gain of the spinal transformation of monosynaptic sensory input into motor output. Our proposed tests of this hypothesis will advance understanding of the important, yet still unresolved relative contributions made by these neural mechanisms to hyper-resistance. Based on our neuromechanical and multiscale modeling advances in the prior funding period, in Aim 1 we will develop a multiscale in silico neuromuscular circuit model to predict how independent changes in alpha- drive, gamma-drive, and sensorimotor gain differentially affect clinically-relevant movements such as the tendon tap and pendulum test. In Aim 2, we will characterize the relative increases in alpha-drive, gamma-drive, and sensorimotor gain across clinically-relevant spinal excitability levels in a living biological neuromuscular circuit in vivo using a decerebrate rat preparation. In Aim 3 we will identify clinically-relevant movement abnormalities across spinal excitability levels in a novel biohybrid robotic system coupling the living neuromuscular circuit (in vivo) to a virtual biomechanical limb (in silico). A robotic controller will enforce the physics of dynamically changing inertial and gravitational forces, allowing movement to emerge from the causal interaction between the in vivo neuromuscular circuit and the virtual limb. Through the close coordination of these Aims, we will establish a computational and experimental framework to address clinical barriers (1) to determine how changes in neural mechanisms and the inertial properties of the limb could correct movement abnormalities, (2) to provide insight into how these mechanisms could be identified through different clinical assessment scenarios, and (3) to compare the relative effects of different treatment targets. The proposed work will likely impact both clinically-relevant human sensorimotor research and basic sensorimotor neuroscience.


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: 2024 ( Subtotal = $576,541 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	001	9	5/7/2024	NON-COMPETING CONTINUATION	$52,413
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	9	4/11/2024	NON-COMPETING CONTINUATION	$524,128
														Subtotal = $576,541

Issue Date FY: 2023 ( Subtotal = $582,364 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	8	4/27/2023	NON-COMPETING CONTINUATION	$582,364
														Subtotal = $582,364

Issue Date FY: 2022 ( Subtotal = $795,470 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	003	7	8/17/2022	SUPPLEMENT FOR EXPANSION	$213,106
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	002	7	4/21/2022	NON-COMPETING CONTINUATION	$582,364
2022	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	001	6	12/10/2021	COMPETING CONTINUATION	$251,666
2022	2020	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	5	12/10/2021	NON-COMPETING CONTINUATION	-$251,666
														Subtotal = $795,470

Issue Date FY: 2021 ( Subtotal = $610,442 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	001	6	6/22/2021	COMPETING CONTINUATION	$610,442
2021	2020	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	5	5/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $610,442

Issue Date FY: 2020 ( Subtotal = $327,117 )
2020	2020	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	5	5/25/2020	NON-COMPETING CONTINUATION	$327,117
														Subtotal = $327,117

Issue Date FY: 2019 ( Subtotal = $331,932 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	4	6/24/2019	NON-COMPETING CONTINUATION	$331,932
														Subtotal = $331,932

Issue Date FY: 2018 ( Subtotal = $336,699 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	3	5/18/2018	NON-COMPETING CONTINUATION	$336,699
														Subtotal = $336,699

Issue Date FY: 2017 ( Subtotal = $342,912 )
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	2	5/25/2017	NON-COMPETING CONTINUATION	$342,912
														Subtotal = $342,912

Issue Date FY: 2016 ( Subtotal = $371,622 )
2016	2016	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Child Health and Human Development Extramural Research	000	1	9/15/2016	NEW	$371,622
														Subtotal = $371,622

Grand Total All Awards = $4,275,099

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Multiscale models of proprioceptive encoding to reveal mechanisms of impaired sensorimotor control

Award Number: R01HD090642

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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