The evolution of direct transcranial photobiomodulation: a history of dose, depth, and delivery

Direct transcranial photobiomodulation (dtPBM) delivers red or near-infrared light through the scalp and skull with the aim of affecting brain tissue. The field has produced encouraging findings but inconsistent clinical results. We reconstruct its development as a history of scientific and engineering decisions in which optical access, target depth, and dose repeatedly shaped what could be tested. The clinical lineage began with light therapy for ischemic myocardium and moved to stroke, where cadaver measurements established that near-infrared light could traverse the human scalp and skull and defined a historical design target of approximately 7.5 mW/cm 2 at the dura. The NEST clinical program then carried a fixed 808-nm regimen into three stroke trials: NEST-1 met its primary endpoint, NEST-2 showed a nonsignificant overall trend (p = 0.094) with a published post hoc signal in moderate stroke (p = 0.044), and NEST-3 stopped for futility. An unpublished, exploratory NEST-2 reanalysis described larger treatment differences for superficial lesions; this observation motivates prospective testing but does not establish depth-dependent efficacy. After NEST, treatment moved to the forehead, where target geometry was more reproducible. The ELATED trials adopted a more practical LED platform at substantially lower irradiance while preserving broadly similar treatment-site radiant exposure, whereas the TRIADE R61 trial deliberately varied optical parameters and found optical-parameter-dependent, bidirectional BOLD power responses. The historical record also leaves biological mechanism unresolved: mitochondrial/redox, neurovascular, glial-inflammatory, network-mediated, and diffuse or systemic pathways remain plausible at different levels of evidence, and a distributed physiological response does not by itself identify where the effect begins. These observations support a constrained historical inference: dose, depth, and delivery site are biological variables, not merely device specifications. We distinguish focal-local, diffuse/systemic, and local-stimulation/network-mediated accounts of action and identify prospective tests that can discriminate among them. The next phase of dtPBM development should prioritize indications in which optical access, target engagement, and a disease-relevant network or biomarker can be specified prospectively rather than inferred after a clinical outcome.