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Neurocognitive research has the potential to identify the relevant effects of music therapy. In this study, we examined the effect of music mode (major vs. minor) on stress reduction using optical topography and an endocrinological stress marker. In salivary cortisol levels, we observed that stressful conditions such as mental fatigue (thinking and creating a response) was reduced more by major mode music than by minor mode music. We suggest that music specifically induces an emotional response similar to a pleasant experience or happiness. Moreover, we demonstrated the typical asymmetrical pattern of stress responses in upper temporal cortex areas, and suggested that happiness/sadness emotional processing might be related to stress reduction by music.