Oxygen and the Spark of Human Brain Evolution: Complex Interactions of Metabolism and Cortical Expansion across Development and Evolution

Andrea I. Luppi*, Fernando E. Rosas, Mary Ann P. Noonan, Pedro A.M. Mediano, Morten L. Kringelbach, Robin L. Carhart-Harris, Emmanuel A. Stamatakis, Anthony C. Vernon, Federico E. Turkheimer

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review


Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development—before and after birth and through maturation to adulthood—and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain—favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for neural plasticity sets the conditions for cognitive flexibility and ongoing learning, supporting complex group dynamics and intergenerational learning that in turn enabled improved nutrition to fuel the metabolic costs of further cortical expansion. Our proposed model delineates explicit mechanistic links among metabolism, molecular and cellular brain heterogeneity, and behavior, which may lead toward a clearer understanding of brain development and its disorders.

Original languageEnglish
Pages (from-to)173-198
Number of pages26
Publication statusPublished - Apr 2024


  • aerobic glycolysis
  • complex systems
  • cortical expansion
  • development
  • evolution
  • metabolism
  • oxygen
  • plasticity
  • social brain
  • transmodal association cortex


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