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Locating the neural substrates for the flexor synergy after stroke

Award Number: R01NS119319
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Locating the neural substrates for the flexor synergy after stroke - A stroke often damages motor areas of the brain. Understandably, this leads to a loss of movement control: the limbs become weak, and movements are slower and less well-coordinated. In addition to loss of function, patients also gain unwanted muscle contractions called synergies. For example, whenever the arm is lifted (shoulder abduction), the elbow flexes. These co-contractions intrude into normal movements. Synergies, not just weakness or lack of control, are a major contributor to disability in stroke survivors. Many previous studies have investigated stroke recovery in animals (typically monkeys because of the close similarities of their motor system to humans), but these have focused on recovery of lost function, not on synergies. One reason is that in most previous work monkeys did not express overt synergies; until now we have therefore lacked a model of one of the major causes of post-stroke disability. This critical gap in our understanding has largely gone unnoticed. We need to know how to induce synergies in monkeys, which neural circuits are responsible for them, how they are controlled in health, and how this control becomes disordered after stroke. This project seeks to address this gap, paving the way for a rational approach to new therapy for synergies. In the first experiment, monkeys will be trained on a reaching task, and then implanted with electrodes to measure muscle activity. High speed video recordings will extract movement kinematics. An instrumented linear motor will measure tendon-tap reflexes. After baseline recordings, we will induce a focal cortical ischemic lesion, and gather further data over the subsequent months. We will measure the development of inappropriate contractions of elbow flexors with shoulder abductors during outward reaches. We will analyze reaching trajectories to quantify quality of movement (equivalent to a dexterity measure in the hand, but for reach). Tendon tap reflexes will assess spasticity. Lesions of five different cortical regions will be compared. The lesion which produces the most severe synergy will then be combined with damage to the magnocellular red nucleus, which we hypothesize will further accentuate synergy expression. This experiment will elucidate the detailed functional anatomy of the post-stroke syndrome, and also yield an optimized monkey model of pathological synergies. In the second experiment, monkeys will be trained to move an on-screen cursor controlled by shoulder abduction-elbow flexion torques into targets, allowing parametric examination of independent versus co- activation. Initially neural circuits will be characterized in healthy monkeys. After necessary surgical implants, neural activity will be recorded from different parts of the motor cortex, the reticular formation, and the spinal cord. We hypothesize that spinal circuits will show neural activity consistent with co-activation of shoulder and elbow muscles to generate synergies; activity in supraspinal areas will be consistent with either driving this spinal circuit, or suppressing it to allow independent muscle activation. Recordings will then be repeated in monkeys subjected to the lesion which generates optimal synergies, to reveal the nature of pathological changes.


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 = $0 )
2026	2025	UNIVERSITY OF NEWCASTLE UPON TYNE	NEWCASTLE UNIVERSITY, KING'S GATE	NEWCASTLE UPON TYNE				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/31/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $457,675 )
2025	2025	UNIVERSITY OF NEWCASTLE UPON TYNE	NEWCASTLE UNIVERSITY, KING'S GATE	NEWCASTLE UPON TYNE				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/29/2025	NON-COMPETING CONTINUATION	$457,675
														Subtotal = $457,675

Issue Date FY: 2024 ( Subtotal = $443,945 )
2024	2024	UNIVERSITY OF NEWCASTLE UPON TYNE	NEWCASTLE UNIVERSITY, KING'S GATE	NEWCASTLE UPON TYNE				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/28/2024	NON-COMPETING CONTINUATION	$443,945
2024	2022	UNIVERSITY OF NEWCASTLE UPON TYNE	NEWCASTLE UNIVERSITY, KING'S GATE	NEWCASTLE UPON TYNE				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $443,945

Issue Date FY: 2023 ( Subtotal = $457,675 )
2023	2023	UNIVERSITY OF NEWCASTLE UPON TYNE	NEWCASTLE UNIVERSITY, KING'S GATE	NEWCASTLE UPON TYNE				GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/13/2023	NON-COMPETING CONTINUATION	$457,675
														Subtotal = $457,675

Issue Date FY: 2022 ( Subtotal = $457,675 )
2022	2022	NEWCASTLE UNIVERSITY	KINGSGATE	NEWCASTLE-UPON-TYNE	TYNE AND WEAR			GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/18/2022	NON-COMPETING CONTINUATION	$411,904
2022	2022	NEWCASTLE UNIVERSITY	KINGSGATE	NEWCASTLE-UPON-TYNE	TYNE AND WEAR			GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/24/2022	NON-COMPETING CONTINUATION	$45,771
														Subtotal = $457,675

Issue Date FY: 2021 ( Subtotal = $460,134 )
2021	2021	NEWCASTLE UNIVERSITY	KING'S GATE	NEWCASTLE-UPON-TYNE	TYNE & WEAR			GBR	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/14/2021	NEW	$460,134
														Subtotal = $460,134

Grand Total All Awards = $2,277,104

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Locating the neural substrates for the flexor synergy after stroke

Award Number: R01NS119319

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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