Summary Being able to noninvasively modulate brain activity, where and when an experimenter desires, with an immediate path towards human translation is a long-standing goal for neuroscience. To enable robust perturbation of brain activity while leveraging the ability of focused ultrasound to deliver energy to any point of the brain noninvasively, we have developed biocompatible and clinically-translatable nanoparticles that allow ultrasound-induced uncaging of neuromodulatory drugs. Utilizing the anesthetic propofol together with electrophysiological and imaging assays, we show that the neuromodulatory effect of ultrasonic drug uncaging is limited spatially and temporally by the size of the ultrasound focus, the sonication timing, and the pharmacokinetics of the uncaged drug. Moreover, we see secondary effects in brain regions anatomically distinct from and functionally connected to the sonicated region, indicating that ultrasonic drug uncaging could noninvasively map the changes in functional network connectivity associated with pharmacologic action at a particular brain target.

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A long-standing goal of translational neuroscience is the ability to noninvasively deliver therapeutic agents to specific brain regions with high spatiotemporal resolution. Focused ultrasound (FUS) is an emerging technology that can noninvasively deliver energy up the order of 1 kW/cm 2 with millimeter and millisecond resolution to any point in the human brain with Food and Drug Administration-approved hardware. Although FUS is clinically utilized primarily for focal ablation in conditions such as essential tremor, recent breakthroughs have enabled the use of FUS for drug delivery at lower intensities (i.e., tens of watts per square centimeter) without ablation of the tissue. In this review, we present strategies for image-guided FUS-mediated pharmacologic neurointerventions. First, we discuss blood-brain barrier opening to deliver therapeutic agents of a variety of sizes to the central nervous system. We then describe the use of ultrasound-sensitive nanoparticles to noninvasively deliver small molecules to millimeter-sized structures including superficial cortical regions and deep gray matter regions within the brain without the need for blood-brain barrier opening. We also consider the safety and potential complications of these techniques, with attention to temporal acuity. Finally, we close with a discussion of different methods for mapping the ultrasound field within the brain and describe future avenues of research in ultrasound-targeted drug therapies.

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Although holistic processing has been documented extensively for upright faces, it is unclear whether it occurs for other visual categories with more extensive substructure, such as body postures. Like faces, body postures have high social relevance, but they differ in having fine-grain organization not only of basic parts (e.g., arm) but also subparts (e.g., elbow, wrist, hand). To compare holistic processing for whole bodies and body parts, we employed a novel stereoscopic depth manipulation that creates either the percept of a whole body occluded by a set of bars, or of segments of a body floating in front of a background. Despite sharing low-level visual properties, only the stimulus perceived as being behind bars should be holistically Bfilled in^via amodal completion. In two experiments, we tested for better identification of individual body parts within the context of a body versus in isolation. Consistent with previous findings, recognition of body parts was better in the context of a whole body when the body was amodally completed behind occluders. However, when the same bodies were perceived as floating in strips, performance was significantly worse, and not significantly different, from that for amodally completed parts, supporting holistic processing of body postures. Intriguingly, performance was worst for parts in the frontal depth condition, suggesting that these effects may extend from gross body organization to a more local level. These results provide suggestive evidence that holistic representations may not be Ball-or-none,^but rather also operate on body regions of more limited spatial extent.