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.

Public Health Relevance

Many stroke survivors face the daily struggle of living with disability; movement synergies are a major contributor to their impairment. Understanding the neural circuits underlying synergies is the first stage of developing rational therapeutic interventions. Our long-term aim is to develop ways of treating synergies at the circuit level (such as neurostimulation to induce plasticity, or specific drugs), freeing patients to improve their function unencumbered by these intrusive and unwanted movement.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Sensorimotor Integration Study Section (SMI)
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Chen, Daofen
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University of Newcastle
Newcastle Upon Tyne
United Kingdom
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