The metabolic layer of cognition: integrating metabolomics, breathomics, and systems neuroscience

Cognitive neuroscience has made substantial progress in mapping neural activity underlying perception, memory, and decision-making. However, widely used methods such as functional magnetic resonance imaging and electrophysiology primarily measure indirect physiological correlates of neuronal activity and provide limited access to the biochemical processes that support neural signaling. In this review, we propose that metabolism might constitutes a critical intermediate layer linking neural activity and behavior. Drawing on advances in metabolomics and breathomics, we examine how mass spectrometry-based analytical techniques enable sensitive detection of metabolites, neurotransmitters, lipids, and volatile organic compounds that could reflect metabolic processes associated with neuronal signaling and cognitive states. We synthesize emerging research at the intersection of neuroenergetics, systems neuroscience, and metabolic profiling, highlighting how these approaches can complement established neuroimaging and electrophysiological methods. In particular, we discuss the potential of volatile organic compounds in exhaled breath as non-invasive indicators of systemic metabolic responses accompanying cognitive processes. At the same time, we address key conceptual and methodological challenges in interpreting peripheral metabolic signals in relation to brain activity, including the influence of systemic physiology, microbiome metabolism, and environmental factors. Finally, we outline future directions for integrating metabolomic and breathomic measurements with neural and behavioral data in multimodal experimental frameworks. Incorporating metabolic dynamics into systems-level models may provide a new perspective on how cognition emerges from interactions between brain activity and whole-body physiology.