Metabolic brain networks switch between a sparsely connected baseline and highly integrated states to support cognition

Abstract

The human brain achieves cognitive flexibility by rapidly switching between large-scale functional network states. While network state switching is assumed to be an energetically demanding process, the direct metabolic and neurochemical foundation underpinning state switching has not been characterised. Here, we combine functional FDG-PET (fPET) imaging and sliding-window analyses to characterise metabolic network state switching in 85 healthy adults (20-86 years). Across the dynamic fPET scan, four recurring metabolic network states were identified: a highly prevalent, sparsely connected baseline state alongside three transient, globally integrated network states of cognitive control and attention. Cognitive performance relied on the capacity to mobilise the integrated and metabolically efficient associative system states. This flexible network switching was directly enabled by the moment-to-moment dynamic range of the underlying regional glucose signals, which supported the brain to move away from the baseline and enabled prolonged dwell times in network states supporting high-order cognition. Neurotransmitter analyses revealed a low-dimensional neurochemical hierarchy governing dynamic the network states, anchored by a dominant axis of endocannabinoid, metabolic, serotonergic and GABAergic systems. Dynamic departures from this stable axis were controlled by a specialised noradrenergic state-switching gate. The dynamic metabolic network architecture was also attenuated in older adults, who exhibited a loss of network flexibility and were anchored to the sparsely connected baseline state. These findings reveal that functional network state switching is an emergent property of the brain's metabolic architecture and that the organisation of large-scale neural networks is constrained by energetic and neurochemical principles. This understanding may provide critical new insights into the metabolic basis of brain ageing, neurodegeneration and psychiatric conditions.