Neuromodulatory Inputs to Motoneurons Contribute to the Loss of Independent Joint Control in Chronic Moderate to Severe Hemiparetic Stroke

Abstract

In chronic hemiparetic stroke, increased shoulder abductor activity causes involuntary increases in elbow, wrist, and finger flexor activation, an abnormal muscle coactivation pattern known as the flexion synergy. Recent evidence suggests that flexion synergy expression may reflect recruitment of contralesional cortico-reticulospinal motor pathways following damage to the ipsilesional corticospinal tract. However, because reticulospinal motor pathways produce relatively weak post-synaptic potentials in motoneurons, it is unknown how preferential use of these pathways could lead to robust muscle activation. Here, we hypothesize that the descending neuromodulatory component of the ponto-medullary reticular formation, which uses the monoaminergic neurotransmitters norepinephrine and serotonin, serves as a gain control mechanism to facilitate motoneuron responses to reticulospinal motor commands. Thus, inhibition of the neuromodulatory component would reduce flexion synergy expression by disfacilitating spinal motoneurons. To test this hypothesis, we conducted a pre-clinical study utilizing two targeted neuropharmacological probes and inert placebo in a cohort of 16 individuals with chronic hemiparetic stroke. Test compounds included Tizanidine (TIZ), a noradrenergic α2 agonist and imidazoline ligand selected for its ability to reduce descending noradrenergic drive, and Isradipine, a dihyropyridine calcium-channel antagonist selected for its ability to post-synaptically mitigate a portion of the excitatory effects of monoamines on motoneurons. We used a previously validated robotic measure to quantify flexion synergy expression. We found that Tizanidine significantly reduced expression of the flexion synergy. A predominantly spinal action for this effect is unlikely because Tizanidine is an agonist acting on a baseline of spinal noradrenergic drive that is likely to be pathologically enhanced post-stroke due to increased reliance on cortico-reticulospinal motor pathways. Although spinal actions of TIZ cannot be excluded, particularly from Group II pathways, our finding is consistent with a supraspinal action of Tizanidine to reduce descending noradrenergic drive and disfacilitate motoneurons. The effects of Isradipine were not different from placebo, likely related to poor central bioavailability. These results support the hypothesis that the descending monoaminergic component of the ponto-medullary reticular formation plays a key role in flexion synergy expression in chronic hemiparetic stroke. These results may provide the basis for new therapeutic strategies to complement physical rehabilitation.

Cross-Frequency Coupling in Descending Motor Pathways: Theory and Simulation

“…This measure could have a significant impact on future neuropathophysiological studies on individuals with an unilateral brain injury, since recent studies have indicated that motor impairments after a unilateral brain injury could be associated with an increased reliance on multi-synaptic indirect motor pathways following a lesion-induced loss of direct corticospinal projections (Owen et al, 2017;McPherson et al, 2018a;Karbasforoushan et al, 2019). Therefore, a measure that quantitatively determines the usage of indirect motor pathways over direct corticospinal drive could be crucial (1) for evaluating motor recovery following unilateral brain injuries, and (2) for determining the effect of targeted therapeutic interventions (Ellis et al, 2018;McPherson et al, 2018b) that aim to reduce the maladaptive reliance on indirect motor pathways after a hemiparetic stroke. In the future, we will examine both crossfrequency and iso-frequency coupling, as well as the COI, between the brain and muscle signals to characterize the relative ratio of the recruitment of indirect vs. direct motor pathways following unilateral brain injuries, such as hemiparetic stroke and unilateral celebral palsy.…”

Biomechanical parameters of the elbow stretch reflex in chronic hemiparetic stroke

“…Indeed, interventions targeting other components of the post-stroke sensorimotor impairment sequelae (e.g., the upper limb flexion synergy) may still impact spinal motor excitability or benefit from a reduction in spinal motor excitability. For example, it has recently been shown that targeted neuropharmacology can reduce flexion synergy expression by disfacilitating spinal alpha motoneurons (McPherson et al 2018a). The protocol described here could provide an efficient additional outcome measure for inferring the nature and extent of changes in spinal motor excitability.…”

“…The contralesional elbow flexors are implicated in a variety of functional impairments arising from changes in spinal motor excitability, including flexion synergy expression and spasticity (Ellis et al 2017; Jin and Zhao 2018; McPherson et al 2018a; McPherson et al 2018b; Sommerfeld et al 2012). We balance the competing needs of efficient implementation and high precision by using a clinically available mechatronic device and biomechanical measures of the stretch reflex response.…”

“…Here, we systematically probe the proportion of reflex-driven movement resistance mathematically accounted for by reflex threshold angle and reflex stiffness in the contralesional elbow flexors of individuals with chronic unilateral brain injury. The contralesional elbow flexors are implicated in a variety of functional impairments arising from changes in spinal motor excitability, including flexion synergy expression and spasticity (Ellis et al 2017; Jin and Zhao 2018; McPherson et al 2018a; McPherson et al 2018b; Sommerfeld et al 2012). We balance the competing needs of efficient implementation and high precision by using a clinically available mechatronic device and biomechanical measures of the stretch reflex response.…”

Linking Motoneuron PIC Location to Motor Function in Closed-Loop Motor Unit System Including Afferent Feedback: A Computational Investigation

“…Functional consequences of neuromodulatory drive versus PIC activation location Recent experimental studies have suggested that the level of neuromodulatory drive from the brain stem may vary depending on the target muscles (Bowker et al 1982;Esposito et al 2014;Powers and Binder 2001) and pathological states (McPherson et al 2018a;McPherson et al 2018b). A recent computational study showed analyzing the open-loop motor unit model how neuromodulatory inputs to motoneurons, including intrinsic inputs from PIC channels at a D path of ~0.6 mm, influence force production by the motor unit during isometric contractions at various muscle lengths (Kim 2017b).…”