Functional connectivity mediates the relationship between cardiorespiratory fitness and stress in midlife.

Background: Increasing evidence suggests that the relation between mental health and physical health is bidi-rectional and underpinned by complex neural systems. Cardiovascular fitness is a key measure of physical health but its relation to mental health is insufficiently examined. Characterizing the neural mechanisms by which cardiovascular fitness influences mental health could inform the development of strategies to promote mental health and minimize the risk of mental disorders.Methods and results: The relation between cardiorespiratory fitness, functional brain connectivity and mental health was studied in 418 healthy middle-aged (aged 40-65 years) adult participants of the Barcelona Brain Health Initiative (BBHI). Higher cardiorespiratory fitness, measured by VO2 peak, was associated with lower symptoms of anxiety (13 =-0.111, p = 0.017) and stress (13 =-0.242, p = 0.002) scores, evaluated by the Depression Anxiety and Stress Scale (DASS-21) and its three subscales (stress, anxiety, and depression). Higher within-network functional connectivity of the Default Mode Network (DMN) was associated with higher VO2 peak (13 = 0.195, p = 0.002), and lower stress scores (13 =-0.126, p = 0.011). In addition, higher functional connectivity between the Frontoparietal Network (FPN) and Salience Network (SN) was associated with higher VO2 peak (13 = 0.187, p = 0.002), and lower stress scores (13 =-0.123, p = 0.016). Both within-DMN [ACME =-0.02 (-0.04,-0.00), p = 0.040] and between FPN-SN [ACME =-0.01 (-0.04,-0.00), p = 0.036] functional connectivity mediated the relationship between cardiorespiratory fitness and stress. Conclusions: The relationship between the cardiorespiratory fitness and stress in middle-aged adults is mediated by functional connectivity of several intrinsic resting-state networks. These results highlight a potential mech-anistic pathway through which higher cardiorespiratory fitness can positively impact brain health in midlife.