UNCOVERING MECHANISMS OF PHOTOBIOMODULATION BEHIND CLINICAL CHANGES: EVIDENCE FROM NEUROIMAGING

The goal of this presentation is to provide mechanistic insight into transcranial photobiomodulation (tPBM)-induced clinical, cognitive, and behavioral changes presented by the other panelists and existing literature. More specifically, it will synthesize findings from tPBM studies (case reports, clinical trials, etc.) that use a variety of neuroimaging modalities, including functional MRI and magnetic resonance spectroscopy, across healthy and psychiatric populations to clarify the neurophysiological mechanisms underlying clinical changes after tPBM. Content will include 1) existing evidence of tPBMinduced neurophysiological changes in both healthy and clinical groups, 2) our team’s ongoing work alongside current clinical trials, and 3) future directions for integrating tPBM into clinical trials based on neuroimaging evidence. While we will discuss a host of findings from our lab and others, we highlight two new studies. Our group’s work and clinical trials span multiple populations, including Alzheimer’s disease, sleep disorders, depression, bipolar disorder, and traumatic brain injury. We show that intrinsic brain activity, measured with MRI-derived fractional amplitude of low-frequency fluctuations (fALFF), may serve as a marker of bioenergetic change after tPBM. We previously reported the first evidence that tPBM increases fALFF in aging individuals with early Alzheimer’s disease (AD) (Gaggi et al., Brain Stim 2024). To further examine metabolic mechanisms, two analyses across three sites assessed whether baseline cerebral metabolism predicts fALFF changes during tPBM in early AD (n=19, mean age 74). Baseline 31P-MRS quantified metabolic status. As shown in prior work, fALFF increased during tPBM in frontal regions irradiated by the laser (e.g., F3: t=−2.29, p=0.03; F4: t=−2.78, p=0.01). In the current analysis, fALFF change correlated with PCR/Pi in regions including F3 (rho=.762, p=.028), F4 (rho=−.833, p=.010), and FP2 (rho=−.786, p=.036). Overall, lower baseline metabolism predicted larger tPBM-related fALFF increases in frontal regions. We also explored the effect of tPBM on fALFF in 12 individuals with major depressive disorder (MDD) using concurrent tPBM-MRI (mean age 36, 70% female, 90% non-Hispanic/Latinx), who underwent three different doses of tPBM vs. sham (voxel-wise paired t-tests). Changes in fALFF during the medium dose appeared in the left thalamus and caudate and right medial frontal and temporal regions (cluster size k > 100; t=3.36, p < .001). fALFF was modulated by the three tPBM doses in MDD, with the medium dose showing the strongest effects and no modulation during sham. Overall, these results support the relationship between fALFF and quantitative measures of cerebral metabolism and show that brain activity can be modulated by tPBM in mood and cognitive disorders, particularly in regions with impaired metabolism showing the most robust increases. By integrating imaging-driven mechanistic insights with emerging clinical evidence, this talk aims to outline a roadmap for advancing tPBM as an informed, mechanism-based intervention for brain health. These findings provide some of the first mechanistic evidence linking tPBM-induced changes in intrinsic brain activity to quantitative markers of cerebral metabolism, identifying potential biomarkers of treatment sensitivity and clarifying how impaired metabolic function may shape neural responsiveness across disorders. By establishing measurable imaging markers and demonstrating dose-dependent neural modulation, this work advances the field toward more precise, mechanism-guided tPBM interventions and more targeted clinical trial design.

References

Gaggi NL, Collins KA, Gonzalez-Castillo J, et al. Transcranial photobiomodulation increases intrinsic brain activity within irradiated areas in early Alzheimer’s disease: potential link with cerebral metabolism. Brain Stimul. 2024;17(2):208– 210. Gaggi NL, Parincu Z, Peterson A, et al. Enhancing sleep, wakefulness, and cognition with transcranial photobiomodulation: a systematic review. Front Behav Neurosci. 2025;19:1542462.