Mitochondrial–neuroimmune interfaces in post-stroke spasticity: from acute brain injury to chronic motor phenotypes

 Survivors would like SPASTICITY CURED! Why aren't you working on that? You're that incompetent you don't know what survivors want?

Mitochondrial–neuroimmune interfaces in post-stroke spasticity: from acute brain injury to chronic motor phenotypes

• 

  Zihang Huang *

• School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, China

Abstract

Post-stroke spasticity is a common and clinically consequential manifestation of the upper motor neuron syndrome, yet its mechanisms are incompletely explained by stretch reflex hyperexcitability alone. Established models emphasize corticospinal and corticoreticulospinal injury, altered brainstem descending drive, spinal reflex amplification, impaired inhibitory control, and secondary changes in skeletal muscle and connective tissue. In parallel, stroke induces profound mitochondrial stress and neuroimmune activation, including bioenergetic failure, mitochondrial reactive oxygen species production, mitochondrial quality-control disturbance, mitophagy dysregulation, mitochondrial danger signaling, glial activation, blood–brain barrier dysfunction, and peripheral immune responses. This Review examines how these mitochondrial–neuroimmune processes may interface with established neural and peripheral mechanisms to shape the onset, persistence, and heterogeneity of post-stroke spasticity. We distinguish strict reflex-mediated spasticity from broader spastic hypertonia, emphasizing that chronic clinical phenotypes often reflect mixed contributions from descending pathway imbalance, spinal disinhibition, spastic dystonia, passive muscle stiffness, pain, and contracture. We propose a brain–spinal cord–muscle framework in which mitochondrial and immune responses after stroke may modify motor-network plasticity, spinal inhibitory remodeling, skeletal muscle metabolism, autophagy-related tissue adaptation, and systemic inflammatory–metabolic vulnerability. Direct PSS-specific evidence remains limited. Accordingly, mitochondrial and neuroimmune pathways are framed here as candidate modifiers of phenotype trajectory rather than as established causes, validated biomarkers, or established therapeutic targets for PSS. The novelty of this Review lies in integrating established circuit and muscle mechanisms with broader stroke mitochondrial–immune biology to define testable interfaces and priorities for longitudinal phenotyping and mechanism-based trials.