Measured per-subject vmPFC fluence (N = 7 AOMIC head models, 1064 nm, Fpz montage) mapped onto the illustrative %ΔCMRO₂ dose-response. Optical levers get light to depth; the deep-targeting adjuncts — tFUS-concentrated methylene blue and deep neuromodulation (any mix of modalities) — add effect where the light can't reach. Dots turn green when they clear the 9% target.
Illustrative metabolic model — magnitudes (R_MAX, F_OPT, M_OPT, synergy) are placeholders to be fit to broadband-NIRS oxidized-cytochrome (oxCCO) data. The 9% target is anchored to the established effect of cortical 1064-nm TILS: a significant, reproducible rise in oxidized cytochrome-c-oxidase (Δ[oxCCO] ≈ 0.08 µM in healthy adults — Wang et al. 2017; reproduced by Pruitt et al. 2020; shown in prefrontal cortex by O'Donnell et al. 2023). The target is to reproduce that proven cortical TILS effect at the vmPFC; the %ΔCMRO₂ magnitude itself awaits direct calibration to the oxCCO dose-response. Cooling headroom is from the Pennes bioheat model (peak-tissue ≤ 6 K; 1× at 37 °C → ~5.5× at 30 °C → ~30× cap ≤ 25 °C, beyond which the limit is MPE, not heating). tFUS concentrates systemic MB focally at the vmPFC via microbubble BBB opening (over-concentration past the ~3 µM optimum falls off — hormetic). Deep neuromodulation adds a light-independent metabolic drive: each modality's drive is discounted by its focality toward the vmPFC (deep TMS 50%, HD-tES 38%, focused-US 90% on-target); modalities combine by summing on-target drive, and the metabolic response peaks at ~0.70 on-target then declines (hormetic) — so over-stacking overshoots.