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.

Ischemic stroke exacts a heavy toll in death and disability worldwide. After ischemic stroke, the accumulation of pathobiomolecules in the brain extracellular space (ECS) will exacerbate neurological damage and cognitive impairment. Photobiomodulation (PBM) has been demonstrated to improve cognitive function in Alzheimer’s disease mouse models by accelerating molecular transportation in the brain ECS. This suggests that PBM may have a potential role in the accumulation of pathobiomolecules in the brain ECS following ischemic stroke. In this study, we developed a PBM therapy apparatus with custom parameters. By evaluating the treatment effect, we identified that 755 nm was the optimal light wavelength for ischemic stroke in rats with transient middle cerebral artery occlusion/reperfusion. Extracellular diffusion and interstitial fluid (ISF) drainage were measured using a tracer-based magnetic resonance imaging method. Our results showed that PBM accelerated molecular transportation in the brain ECS and ISF drainage, promoting the clearance of pro-inflammatory cytokines and reducing the deposition of pathological proteins. Consequently, the infarct volume decreased and neurological cognitive function was improved. Besides, the acceleration of ISF drainage was achieved by reducing expression and restoring polarization of aquaporin 4 (AQP4) in the peri-infarct area. In summary, we demonstrated that PBM could alleviate ischemia–reperfusion injury and prevent post-stroke cognitive impairment by accelerating molecular transportation in the brain ECS, paving a pathway for ischemic stroke treatment via the light–ECS interaction.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for Parkinson’s disease (PD). However, the therapeutic mechanisms remain incompletely understood, particularly regarding the extracellular space (ECS), a critical microenvironment where molecular diffusion and interstitial fluid (ISF) dynamics are essential for neural function. This study aims to explore the regulatory mechanisms of the ECS in the substantia nigra (SN) of PD rats following STN-DBS. To evaluate whether STN-DBS can modulate ECS diffusion and drainage, we conducted quantitative measurements using a tracer-based magnetic resonance imaging. Our findings indicated that, compared to the PD group, STN-DBS treatment resulted in a decreased diffusion coefficient (D^*), shorted half-life (T_1/2), and increased clearance coefficient (k′) in the SN. To investigate the mechanisms underlying these changes in molecular diffusion, we employed enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and microdialysis techniques. The results revealed that STN-DBS led to an increase in hyaluronic acid content, elevated expression of excitatory amino acid transporter 2 (EAAT2), and a reduction in extracellular glutamate concentration. Additionally, to further elucidate the mechanisms influencing ISF drainage, we employed immunofluorescence and immunohistochemical techniques for staining aquaporin-4 (AQP-4) and α-synuclein. The results demonstrated that STN-DBS restored the expression of AQP-4 while decreasing the expression of α-synuclein. In conclusion, our findings suggest that STN-DBS improves PD symptoms by modifying the ECS and enhancing ISF drainage in the SN regions. These results offer new insights into the mechanisms and long-term outcomes of DBS in ECS, paving the way for precision therapies.

Top-down attention mechanisms require the selection of specific objects or locations; however, the brain mechanism involved when attention is allocated across different modalities is not well understood. The aim of this study was to use functional magnetic resonance imaging to define the neural mechanisms underlying divided and selective spatial attention. A concurrent audiovisual stimulus was used, and subjects were prompted to focus on a visual, auditory and audiovisual stimulus in a Posner paradigm. Our behavioral results confirmed the better performance of selective attention compared to devided attention. We found differences in the activation level of the frontoparietal network, visual/auditory cortex, the putamen and the salience network under different attention conditions. We further used Granger causality (GC) to explore effective connectivity differences between tasks. Differences in GC connectivity between visual and auditory selective tasks reflected the visual dominance effect under spatial attention. In addition, our results supported the role of the putamen in redistributing attention and the functional separation of the salience network. In summary, we explored the audiovisual top-down allocation of attention and observed the differences in neural mechanisms under endogenous attention modes, which revealed the differences in cross-modal expression in visual and auditory attention under attentional modulation.