Movement discoordination following stroke is caused by the emergence of stereotypic multi-joint movement patterns, reflecting a loss of independent joint control, and hyperactivity of spinal reflexes including the stretch reflex (spasticity) and the flexion withdrawal reflex. The commonality between the emergence of abnormal synergies and spinal reflex hyperexcitability following stroke is postulated to arise from an increased bulbospinal monoaminergic drive to the spinal cord following a loss of corticospinal and corticobulbar projections. Evidence for increased bulbospinal input include increased motoneuron excitability, depressed short latency and enhanced long latency flexion reflexes, and a diminished capacity for selective movement due to the emergence of stereotypic synergic movement patterns. We propose to examine the effect of an increased bulbospinal monoaminergic drive on the expression of abnormal movement patterns and spinal reflexes following stroke by manipulating the neural excitability at the spinal cord and/or brainstem using either Tizanidine (TIZ) or Tamsulosin (TAM). It is our intention to: 1) identify and quantify the presence of increased noradrenergic input to the spinal cord following a stroke; 2) elucidate mechanisms underlying hyperactive flexion and stretch reflexes following stroke; 3) investigate the role of monoaminergic pathways in the expression of abnormal muscle and torque synergies under isometric and dynamic conditions in the paretic upper limb following stroke. We predict that inhibition of brainstem monoaminergic pathways as well as group II and high threshold afferents at the cord, through administration of a noradrenergic (NE) a-2 agonist (TIZ), will result in the reduction of discoordination, flexion reflexes and spasticity in individuals with stroke. We also predict that reduction of NE mediated excitation of motoneurons, through the administration of a selective NE a-1 antagonist (TAM), will result in the reduction of volitional strength, spasticity, and magnitude of the flexion reflex. Upper extremity discoordination is expected to remain unaltered by the administration of TAM because of its lack of supraspinal effects. The knowledge generated by this study seeks to reveal the primary mechanisms underlying the presence of discoordination and hyperactive spinal reflexes following stroke. The identification of these mechanisms may direct the development of novel pharmacological agents that target bulbospinal mechanisms underpinning upper extremity discoordination ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054269-02
Application #
7122497
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Chen, Daofen
Project Start
2005-09-15
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$288,253
Indirect Cost
Name
Northwestern University at Chicago
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
McPherson, Jacob G; McPherson, Laura M; Thompson, Christopher K et al. (2018) Altered Neuromodulatory Drive May Contribute to Exaggerated Tonic Vibration Reflexes in Chronic Hemiparetic Stroke. Front Hum Neurosci 12:131
McPherson, Jacob G; Ellis, Michael D; Harden, R Norman et al. (2018) Neuromodulatory Inputs to Motoneurons Contribute to the Loss of Independent Joint Control in Chronic Moderate to Severe Hemiparetic Stroke. Front Neurol 9:470
Stienen, Arno H A; McPherson, Jacob G; Schouten, Alfred C et al. (2011) The ACT-4D: a novel rehabilitation robot for the quantification of upper limb motor impairments following brain injury. IEEE Int Conf Rehabil Robot 2011:5975460
McPherson, Jacob G; Stienen, Arno H A; Drogos, Justin M et al. (2011) The relationship between the flexion synergy and stretch reflexes in individuals with chronic hemiparetic stroke. IEEE Int Conf Rehabil Robot 2011:5975516
McPherson, Jacob G; Ellis, Michael D; Heckman, C J et al. (2008) Evidence for increased activation of persistent inward currents in individuals with chronic hemiparetic stroke. J Neurophysiol 100:3236-43