Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer's disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer's disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Solid nanogenerators often have limited charge transfer due to their low contact area. Liquid-liquid nanogenerators can transfer a charge better than the solid-solid and solid-liquid counterparts. However, the precise manipulation of the liquid morphology remains a challenge because of the fluidity limits of the liquid. In this work, using the surface tension of a droplet to fix its shape, a liquid-liquid triboelectric nanogenerator in Contact-Separation mode is designed using an immiscible aqueous-aqueous interface, achieving a contact surface charge transfer of 129 nC for a single droplet. The configuration is proven to be applicable in humid environments, and the two-phase materials have good biocompatibility and can be used as an effective drug carrier. Therefore, this nanogenerator is useful for designing future implantable devices. Meanwhile, this design also establishes the foundation of aqueous electronics, and additional applications can be achieved using this route.