A Potential Metabolic Basis for Brain Activity Changes After Transcranial Photobiomodulation in Alzheimer’s Disease

Introduction: Transcranial photobiomodulation (t-PBM) is a non-invasive metabolic neuromodulation technique intended to enhance cerebral bioenergetics by stimulating mitochondrial activity. To characterize both baseline metabolic vulnerability and real-time metabolic engagement during stimulation, this preliminary study integrated phosphorus magnetic resonance spectroscopy (31P-MRS) with resting-state fMRI. Methods: Eleven individuals with mild cognitive impairment (MCI) or early Alzheimer’s disease underwent 31P-MRS to quantify baseline cerebral metabolism (PCr/Pi, pH), followed by MRI sessions during which t-PBM was applied over bilateral frontal sites. Fractional amplitude of low-frequency fluctuations (fALFF), a resting-state index strongly associated with cerebral glucose metabolism, was used as a real-time proxy of metabolic change during stimulation. Results: Linear regression analyses indicated that lower baseline PCr/Pi and lower pH, markers of impaired oxidative metabolism, predicted greater increases in fALFF during t-PBM, most prominently in the right frontal pole (FP2) and, to a lesser extent, right dorsolateral prefrontal cortex (F4). While greater dementia severity also predicted larger fALFF responses in select regions, our findings suggest that t-PBM can boost metabolism in some brain regions where it is compromised, but that this may be independent of cognitive function in early AD/MCI. These findings suggest that t-PBM may preferentially engage brain regions with reduced metabolic capacity to exhibit stronger acute responses. Discussion: Overall, these hypothesis-generating results support the combined use of 31P-MRS and fALFF as complementary biomarkers to quantify baseline metabolic status and real-time target engagement. A single session of t-PBM produced neural activity changes consistent with partial metabolic normalization in vulnerable cortical regions. As these results are preliminary, ongoing longitudinal work with a larger cohort will determine whether baseline metabolic profiles and acute fALFF responses predict clinical outcomes after repeated t-PBM treatment.