Brain extracellular space from an overlooked dimension to catalyst of a novel neuroscience paradigm

Therapeutic development for central nervous system disorders has long been characterized by low translational efficiency. Despite sustained advances in basic neuroscience and substantial industrial investment, the clinical benefits achieved in major disease areas, including Alzheimer’s disease, stroke, and psychiatric disorders, remain limited. Existing neuroscience frameworks have primarily centered on neurons, glial cells, and vascular networks, whereas the brain extracellular space (ECS), a core anatomical component of the interstitial system, has not been adequately incorporated into mainstream research and evaluation paradigms. The ECS is critically involved in molecular diffusion, metabolic waste clearance, and post–blood–brain barrier drug transport, and it also represents an essential structural determinant of brain homeostasis and disease progression. Although the ECS occupies approximately 6%–25% of living brain volume, its representation in the broader neuroscience literature remains disproportionately low, indicating a persistent structural blind spot in the field. “Recent advances in high-resolution electron microscopy, super-resolution optical imaging, tracer-based MRI, and AI-assisted quantitative analysis have substantially improved the feasibility of ECS characterization, thereby providing the methodological basis for reintegrating the ECS into studies of CNS disease mechanisms, therapeutic design, and regulatory evaluation. ” said the author Hongbin Han, a researcher at Peking University Third Hospital, “This article provides an overview of the structural and functional characteristics of the extracellular space in brain cells in central nervous system diseases, the historical and technical reasons for its long-term neglect, and its potential significance in elucidating disease mechanisms, optimizing treatment strategies, and reconstructing neuroscience research paradigms.”

This review is organized around three interconnected dimensions of brain extracellular space (ECS) research: measurement and characterization, mechanistic discovery, and therapeutic translation. At the methodological level, the article systematically surveys the development of both tracer-based and label-free approaches, including RTI-TMA+, IOI, TB-MRI, electron microscopy, SUSHI, and diffusion MRI–based methods such as DTI-ALPS, NODDI, and MDI, highlighting how recent advances in high-resolution imaging, AI-assisted reconstruction, and multicompartment quantification have transformed the ECS from a poorly accessible “void” into a structurally and functionally measurable domain. At the mechanistic level, the review synthesizes emerging findings on ECS parcellation, substance transport, and active modulation, showing that the ECS is not merely a passive diffusion space but a dynamic compartment involved in clearance, microenvironmental homeostasis, and reciprocal interactions with neurons, glial cells, and microvasculature, while undergoing marked structural and functional remodeling during aging and disease progression. The discussion is then extended to major neurological disorders, including Alzheimer’s disease, ischemic stroke, multiple sclerosis, schizophrenia, and epilepsy, where ECS abnormalities are linked to impaired protein clearance, inflammatory propagation, restricted drug diffusion, and the formation of pathological microenvironments, thereby supporting the translational potential of ECS-targeted interventions, precision drug delivery, and neuromodulatory strategies. On this basis, the review ultimately advocates replacing the traditional “cell–vasculature” model with an integrated “cell–ECS–vasculature” framework, in which the ECS is formally incorporated into mechanistic research, therapeutic evaluation, clinical trial design, and regulatory assessment for CNS diseases.

Overall, this review elevates the extracellular space (ECS) of brain cells from a long-marginal anatomical and physiological space to an important theoretical dimension for explaining the low conversion efficiency of central nervous system diseases. Based on this, it proposes a "cell–ECS–vasculature" integrated framework to correct the limitations of traditional neuroscience research, which overly focuses on cells and blood vessels while neglecting the transport of substances and the microenvironment structure within the brain. The review further indicates that recent progress in high-resolution imaging, quantitative measurement, and multimodal analytical methods has made it technically feasible to incorporate the ECS into studies of disease mechanisms, drug delivery design, efficacy evaluation, clinical trial methodology, and regulatory assessment. Its contribution, therefore, lies not merely in filling a conceptual gap, but in providing a new structural foundation for precision therapeutics, early-stage screening, and paradigm renewal in CNS research. “In addition, the formal integration of ECS knowledge into medical education and standardized research frameworks may promote a broader methodological transition in neuroscience from localized structural description toward cross-scale systems integration.” said Hongbin Han.

Authors of the paper include Hongbin Han, Hui Dai, Leonor Serrano Lopes, Ruiqing Ni, Benjamin F. Combes, Yangjing Song, Hanbo Tan, Meng Xu, Hongfeng Li, Shuhong Lv, Zhaohe Yang, Tianzi Gao, Mengyu Zhang, Yang Shi, Jingjing Shao, Yanni Zhang, and Wanyi Fu.

This work was supported in part by the Major Program of the National Natural Science Foundation of China (nos. 62394314, 62394311,62394312,62394313, 62394310, and T2442017). We thank M. Jiang, Y. Fu, Z. Tong, Y. Hou, C. Li, J. Zhang, C. Wang, H. Liu, Y. Gao, Z. Xie, X. Liu, and B. Xiong for invaluable contributions.

The paper, “Brain Extracellular Space From an Overlooked Dimension to Catalyst of a Novel Neuroscience Paradigm” was published in the journal Cyborg and Bionic Systems on Mar 4, 2026, at https://spj.science.org/doi/10.34133/cbsystems.0529.

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