This study will target a critical knowledge gap in our understanding of the neural mechanisms underlying upper
limb poststroke spasticity, by directly assessing the descending motor and ascending sensory pathways in
hand function. Spasticity is one of the major motor impairments after stroke that typically begins to emerge
several weeks poststroke, impedes upper limb functional recovery, and gives rise to complications such as
weakness, contractures, and pain. It is traditionally characterized by a velocity-dependent increase in muscle
tone (hypertonia) and increased spinal stretch reflex (hyperreflexia). Although the peripheral and spinal
signatures of spasticity have been extensively studied, its underlying brain mechanisms and brain-spinal
pathways are still controversial. This understanding is critically needed for resolving the current limitations in
clinical management of spasticity related to its early diagnosis, identification of prognostic factors, and lack of
effective treatments targeting the origin of the impairments rather than its symptoms. Preclinical studies have
shown that lesions of descending motor pathways including the reticulospinal tract (RST) may lead to spastic
hypertonia after stroke. In contrast, changes in the spinal sensory-motor circuits and the ascending sensory
projections may underlie hyperreflexia after stroke. Yet it is unclear how brain lesions after stroke lead to these
remote changes in the spinal cord circuit. Several theoretical models backed by early electrophysiological work
in cats propose that an imbalance of inhibitory and excitatory projections from the dorsal and medial RST plays
a critical role in spasticity. However, emerging evidence in primates suggests that the type of RST projections
(inhibitory/excitatory) does not follow a dorsal/medial organization, as presumed in current models of spasticity,
but depends on the laterality of projections. In this proposal, we aim to translate these new findings to humans,
and examine their relevance in poststroke spasticity. Our central hypothesis is that in stroke survivors with
spasticity, the imbalanced activation of ipsilateral vs contralateral RST is directly related to spastic hypertonia,
while the hyperactivity of dorsal column somatosensory projections is related to spastic hyperreflexia. To test
this hypothesis, we will employ a powerful neuroimaging method using simultaneous spinal cord–brain
functional magnetic resonance imaging (fMRI) in chronic hemiplegic stroke patients with and without upper
limb spasticity, as well as healthy controls. Using this method, we will assess the function of major descending
(corticospinal, RST) and ascending (dorsal column, anterolateral tract) pathways during hand motor and
sensory functional tasks. We will determine how these neuroimaging markers relate to spastic hypertonia and
hyperreflexia, as evaluated by reliable biomechanical and electrophysiological measurements. Overall, the
proposed projects will advance our understanding of the neurobiological basis of poststroke spasticity, offer
new quantitative neuroimaging markers for accurate prognosis of spastic complications, and provide outcome
measures for evaluating what treatments most directly target the neural origins of spasticity.
