Brain Extracellular Space: From an Overlooked Dimension to Catalyst of a Novel Neuroscience Paradigm

Despite huge investment, therapies for brain disorders remain largely ineffective in clinical practice. Accumulating evidence indicates that this low translational success is closely linked to the long-standing overlook of the brain extracellular space (ECS) in preclinical research, clinical practice, and regulatory frameworks. After over 4 decades of scientific exploration, particularly with recent breakthroughs in imaging and quantitative measurement methods, it is timely to integrate the ECS into the current neuroscience framework. This paper investigates underlying determinants of low translational success of central nervous system drugs and therapeutic devices, reviews the historical and technical bottlenecks that lead to the neglect of ECS research, and emphasizes its transformative potential in reshaping therapeutic strategies. We propose incorporating the ECS into neuroscience research, clinical regulatory assessment, and medical education, thereby establishing a comprehensive paradigm that omits no physical space for precision therapeutics targeting brain disorders.