Beginning in the 1960s, animal and cell culture studies have demonstrated that transcranial photobiomodulation (t-PBM), which involves photons in the red and near-infrared spectrum, can penetrate the cerebral cortex and enhance the mitochondrial electron transport chain [1] (fNIRS similarly uses near infrared photons to image the brain, but at lower light intensities and exposure, resulting in minimal impact on brain function). Emerging human t-PBM data have demonstrated behavioral and clinical effects in multiple patient populations, along with effects on cerebral metabolism and hemodynamics, highlighting its potential therapeutic efficacy [1]. For example, small studies suggested that t-PBM delivered with both high (700 mW/cm2) and low (36 mW/cm2) irradiance [2] is effective in the treatment of major depressive disorder (MDD). However, since other studies with low t-PBM irradiance (55 mW/cm2) did not replicate the positive results in MDD [3], it becomes critically important to further understand the irradiance dose-dependent neurobiological mechanisms of t-PBM, as we are attempting in our ongoing clinical trial [4].

t-PBM has an excellent safety profile [1,2,3], and it can be performed in multiple settings, including during magnetic resonance imaging (MRI) or other neuroimaging modalities, to quantify the impact on brain bioenergetics noninvasively and in real-time. However, work is still underway to determine the optimal parameters for clinical utility. Our team has recently demonstrated the effect of t-PBM, at medium irradiance (300 mW/cm2), on regional intrinsic brain activity in 19 individuals with early Alzheimer’s disease [AD] [5]. In this publication [5], we found that t-PBM altered the fractional amplitude of low-frequency fluctuations (fALFF) across all laser-irradiated brain cortical regions, which are limited to frontal regions due to skull density and hair interference. fALFF, assessed non-invasively during resting-state MRI, is a voxel-based measure of intrinsic brain activity measuring the regional brain metabolism: it is strongly correlated with cerebral glucose metabolism measured by [18F]Fluorodeoxyglucose positron emission tomography. Similarly, other studies have reported increases in MRI BOLD signal (also in t-PBM-irradiated brain areas, at 300 mW/cm2 irradiance) in healthy volunteers [6]. The increase in fALFF we detected in t-PBM-irradiated brain areas during stimulation [5], and the similar increases in MRI BOLD signal [6], suggest that t-PBM can increase intrinsic brain activity (and specifically cerebral metabolism) in real time; these effects continue briefly after t-PBM administration has ended.

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