Frequency Mismatch Critically Limits Gamma Entrainment: A Kuramoto Model Study Supporting Personalized GENUS Therapy

Gamma oscillations (30-100 Hz) are critical for cognitive processing, and their disruption is associated with Alzheimers disease (AD) and related dementias. Gamma ENtrainment Using Sensory Stimulation (GENUS) therapy applies 40 Hz light and/or sound to restore gamma oscillations, but clinical trials report highly variable responses. Using Kuramoto oscillator models calibrated to human neurophysiology, we demonstrate that frequency mismatch between stimulation frequency and individual intrinsic gamma frequency (IGF) is a critical determinant of entrainment efficacy. A 2 Hz frequency mismatch reduced phase-locking value (PLV) by 43-82%, depending on neural resonance bandwidth, with PLV at mismatch indistinguishable from the finite-sample noise floor -- indicating complete absence of stimulus-synchronized oscillation. In a simulated population with IGF drawn from a clinically realistic distribution (mean 35.10 {+/-} 3.49 Hz, N = 200), fixed 40 Hz stimulation achieved mean PLV of 0.119 {+/-} 0.081, compared to 0.504 {+/-} 0.009 for individualized frequency stimulation -- a 4.2-fold advantage (t(199) = 67.26, p < 0.001, Cohens d = 4.76). In the clinically relevant subgroup with IGF < 36 Hz (62% of the population), the fold advantage increased to 5.3x. Stochastic noise sensitivity analysis confirmed robustness of the fold advantage (3.8-4.0x across{sigma}{square}{square}{square}{square}{square}{square} = 0-2.0 rad/s; p < 10{square}3{superscript 1} at all levels). These findings provide quantitative computational support for personalized GENUS protocols incorporating individual gamma frequency measurement and carry direct implications for the design of next-generation clinical trials.