Inhibition/excitation balance is associated with functional connectivity during cognitive flexibility performance.

The primary excitatory and inhibitory neurotransmitters, glutamate and GABA, regulate neural communication. In this cross-sectional study, we investigated whether the large-scale functional connectivity of two important brain hubs, the inferior frontal cortex and the inferior parietal lobe, is associated with changes in the GABA/Glx (glutamate + glutamine) balance in the in vivo human brain during a cognitive flexibility task. Furthermore, we explored age differences in this relationship, given the alterations in neurotransmitter levels and in cognitive flexibility performance in older adults. Forty young (18-35 years; 26 females) and forty older (60-85 years; 21 females) adults participated. The MRI protocol included functional MRI and baseline and task-related magnetic resonance spectroscopy. Results showed that task-induced modulation of GABA+/Glx is associated with functional connectivity from the inferior frontal cortex and inferior parietal lobe during cognitive flexibility performance. In particular, young adults showed stronger functional connectivity associated with increased inhibitory tone in the inferior frontal cortex than older adults, whereas the pattern was reversed in the inferior parietal lobe. In addition, whereas the connectivity between the left inferior parietal lobe and the bilateral putamen in young adults predicted better cognitive flexibility (left putamen: r = 0.41, P = 0.05; right putamen: r = 0.51 P = 0.01; controlling for GABA modulation), this relationship had an opposite direction in older adults (left putamen: r = -0.33, P = 0.05; right putamen: r = -0.31 P = 0.01; controlling for GABA modulation). In sum, these results show that neurometabolic dynamics and functional connectivity underlying cognitive flexibility undergo substantial changes during ageing.