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  • Dynamic Systems Modeling of Transient Photobiomodulation and Persistent Meningeal Lymphatic Endothelial Activation

  • Fathabadi Amirhossein,1 Alikhanzadeh Mona,2 Sharif Samaneh,3 Imanparast Armin,4 Shirokov Alexander,5 Sazgarnia Ameneh,6,*
    1. Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
    2. Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
    3. Medical Genetics Research Center, Mashhad University of Medical Sciences, P. O. Box 9177949224, Mashhad, Iran
    4. Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
    5. Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
    6. Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran


  • Introduction: Background: Meningeal lymphatic vessels (MLVs) support cerebrospinal fluid drainage, macromolecular clearance, and neuroimmune communication. Photobiomodulation (PBM) can enhance MLV drainage and brain macromolecular clearance, but how a transient light stimulus produces a sustained endothelial response remains unclear. Understanding this response may help define the mechanisms underlying PBM-associated lymphatic remodeling.
  • Methods: Methods: A Boolean network was constructed to represent a qualitative sequence from PBM through mitochondrial, redox, inflammatory, cytoskeletal, junctional, mechanosensitive, and drainage states. A transient three-step PBM input was simulated under wild-type, ACTB-clamped, IL6-clamped, and memory-free conditions. An auxiliary memory variable was introduced to test whether a persistence state could maintain downstream activation after stimulus withdrawal. A reduced continuous ordinary differential equation (ODE) model was then developed to describe cytokine signaling, actin remodeling, and drainage enhancement following a 3-h PBM pulse. Selected parameters were optimized using a Tree-structured Parzen Estimator, and persistence was evaluated using an operational actin threshold with sensitivity analysis.
  • Results: Results: The Boolean model produced sequential propagation from PBM through COX4I1, reactive oxygen species, HIF1A, inflammatory signaling, STAT3, ACTB, CTNNB1, permeability, shear stress, KLF2, and modeled drainage. ACTB activation occurred at approximately t=6 and downstream drainage at t=10. Clamping ACTB terminated the downstream cascade before permeability and drainage activation, whereas IL6 clamping was compensated by the parallel TNF branch. After stimulus withdrawal, the memory-free model progressively returned toward the inactive state, while inclusion of the auxiliary memory state maintained downstream activation. The continuous ODE model predicted an above-threshold actin-state interval of approximately 27.1 h for A(t)>0.5, including approximately 25 h after withdrawal of the 3-h stimulus. Sensitivity analysis showed shorter and longer persistence intervals at higher and lower thresholds, respectively.
  • Conclusion: Conclusion: Complementary Boolean and ODE models support a testable systems-level hypothesis in which transient PBM signaling can propagate through inflammatory and cytoskeletal states to produce prolonged modeled endothelial activity. ACTB emerged as an important structural state, while TNF provided modeled redundancy under IL6 perturbation. The predicted persistence interval is a model-derived quantity rather than a measured biological timescale and provides a quantitative hypothesis for future time-resolved experimental studies.
  • Keywords: Photobiomodulation; meningeal lymphatic vessels; computational modeling; Boolean modeling; ordinary

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