Abstract
Photobiomodulation (PBM), the therapeutic application of red to near-infrared light, has demonstrated neuroprotective effects in preclinical CNS models, yet clinical translation remains inconsistent. This systematic review synthesises evidence for PBM across CNS applications to identify factors associated with therapeutic response. We searched five databases (MEDLINE, Embase, CENTRAL, Web of Science, Scopus) through January 2025 following PRISMA 2020 guidelines. Included studies employed PBM for CNS conditions with quantified neurological, cognitive, or functional outcomes; evidence quality was assessed using RoB 2, ROBINS-I, SYRCLE, and the GRADE framework. Thirty studies met inclusion criteria: 27 human studies (n ≈ 2244 participants) and 3 animal studies spanning Alzheimer’s disease, Parkinson’s disease, stroke, traumatic brain injury, and other CNS conditions. Dosimetry—particularly irradiance and light source type (laser vs. LED)—appears to be the primary factor associated with efficacy for Alzheimer’s disease (GRADE: Moderate); trans-cranial LED shows promise for Parkinson’s disease (GRADE: Low); trans-cranial 808 nm laser demonstrates no benefit for acute ischaemic stroke (GRADE: High). Systemic abscopal mechanisms may offer additional therapeutic pathways warranting investigation. These findings provide a condition-specific framework for rational PBM protocol development, supporting adequate irradiance via laser or intra-nasal delivery for Alzheimer’s disease, LED-based trans-cranial protocols for Parkinson’s disease, and integration of artificial intelligence for personalised optimisation.