Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.

Abstract

White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.