Development of a Systems Medicine Approach to Spinal Cord Injury

James D. Guest*, Margot Kelly-Hedrick, Theresa Williamson, Christine Park, Daniyal Mansoor Ali, Ahilan Sivaganesan, Chris J. Neal, Charles H. Tator, Michael G. Fehlings

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Traumatic spinal cord injury (SCI) causes a sudden onset multi-system disease, permanently altering homeostasis with multiple complications. Consequences include aberrant neuronal circuits, multiple organ system dysfunctions, and chronic phenotypes such as neuropathic pain and metabolic syndrome. Reductionist approaches are used to classify SCI patients based on residual neurological function. Still, recovery varies due to interacting variables, including individual biology, comorbidities, complications, therapeutic side effects, and socioeconomic influences for which data integration methods are lacking. Infections, pressure sores, and heterotopic ossification are known recovery modifiers. However, the molecular pathobiology of the disease-modifying factors altering the neurological recovery-chronic syndrome trajectory is mainly unknown, with significant data gaps between intensive early treatment and chronic phases. Changes in organ function such as gut dysbiosis, adrenal dysregulation, fatty liver, muscle loss, and autonomic dysregulation disrupt homeostasis, generating progression-driving allostatic load. Interactions between interdependent systems produce emergent effects, such as resilience, that preclude single mechanism interpretations. Due to many interacting variables in individuals, substantiating the effects of treatments to improve neurological outcomes is difficult. Acute injury outcome predictors, including blood and cerebrospinal fluid biomarkers, neuroimaging signal changes, and autonomic system abnormalities, often do not predict chronic SCI syndrome phenotypes. In systems medicine, network analysis of bioinformatics data is used to derive molecular control modules. To better understand the evolution from acute SCI to chronic SCI multi-system states, we propose a topological phenotype framework integrating bioinformatics, physiological data, and allostatic load tested against accepted established recovery metrics. This form of correlational phenotyping may reveal critical nodal points for intervention to improve recovery trajectories. This study examines the limitations of current classifications of SCI and how these can evolve through systems medicine.

Original languageEnglish
Pages (from-to)1849-1877
Number of pages29
JournalJournal of Neurotrauma
Volume40
Issue number17-18
DOIs
StatePublished - 1 Aug 2023
Externally publishedYes

Keywords

  • allostatic
  • biomarker
  • homeostasis
  • prognosis
  • spinal cord injury
  • systems biology

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