This research was designed to determine whether disrupting the blood-brain barrier (BBB) in rats by applying focused ultrasound (FUS) combined with microbubbles induced changes in the density of caveolae and/or the expression of the structural protein caveolin-1. To this end, two approaches were utilized. First, using enhanced magnetic resonance imaging, characteristics of BBB disruption induced by our specific FUS parameters and dose of microbubble were recorded, and the time after treatment when the BBB was the most permeable was determined. Second, rats were treated with FUS or microbubbles alone, both or neither, and a combination of Evans blue (EB) BBB permeability assays, streptavidin-peroxidase (SP) immunohistochemistry, western blot, and transmission electron microscopy (TEM) was employed to detect any changes in caveolae density and caveolin-1 expression at the previously determined time point when the BBB was the most permeable. The first set of studies revealed that our specific FUS parameters and dose of microbubbles were able to induce a transient, targeted, and reversible BBB opening in rats, and that the BBB was the most permeable 1 h after treatment with FUS and microbubbles. In the second set of experiments, the results of the SP immunohistochemistry, western blot, and TEM, taken together, revealed that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all of the rats regardless of treatment, and that caveolin-1 expression was highest in the rats treated with both FUS and microbubbles. In summary, treatment with FUS, in combination with a dose of microbubbles, can enhance BBB permeability through a caveolae-mediated transcellular approach by upregulating the expression level of caveolin-1 and, consequently, the amount of caveolae. This caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways to induce opening of the BBB. This research sheds light on the mechanism of a transient, targeted, and reversible opening of the BBB induced by FUS combined with microbubbles.

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Magnetic resonance imaging-guided FUS can disrupt the BBB reversibly and deliver IV administered MTX to targeted brain locations; it brings about a greater than 10-fold increase in the drug level and is much more effective (approximately 3.7-fold) than drug delivery through the ICA without sonication. This may facilitate the development of improved treatment methods for central nervous system disorders.

Magnetic resonance imaging-guided focused ultrasound can disrupt the BBB reversibly and can allow targeted delivery of some molecules that normally cannot cross the BBB to locations in the brain. Changes in BBB permeability develop within minutes after sonication as a result of a combination of factors. The BBB has a self-repairing characteristic, which is activated after ultrasound sonication. This may offer an improvement in future clinical applications for central nervous system diseases.

Sleep deprivation (SD) has been reported to severely affect executive function, and interindividual differences in these effects may contribute to the SD-associated cognition impairment. However, it is unclear how individual differences in chronotypes (morning-type, MT; evening-type, ET) influence neurobehavioral functions after SD. To address this question, we used functional magnetic resonance imaging (fMRI) to evaluate whether 24 h of SD differentially affect response inhibition, a core component of executive function, in MT and ET individuals. Accordingly, MT and ET participants were instructed to follow their preferred 7–9-h sleep schedule for 2 weeks at home both prior to and throughout the course of the study, and then performed a go/no-go task during fMRI scanning at 08:00 a.m. both at rested wakefulness (RW) and following SD. We also examined whether the neurobehavioral inhibition differences in the chronotypes in each session can be predicted by subjective ratings (sleepiness, mood, and task) or objective attention. Behaviorally, SD led to an increased response time of go trials (hit RT), more attentional lapses, higher subjective sleepiness, and worse mood indices, but it did not impair the accuracy of go trials (hit rate) and no-go trials (stop rate). Regardless of the presence of SD, ET individuals exhibited a lower stop rate, higher subjective ratings of sleepiness, exhausted mood, and task difficulty in comparison with MT individuals. On the neural level, SD resulted in decreased inhibition-related activation of the right lateral inferior frontal gyrus (rIFG) in MT individuals and increased rIFG activation in ET individuals. Moreover, the rIFG activation in ET individuals after SD was positively correlated to the subjective ratings of sleepiness and effort put into the task, which was considered as a compensatory response to the adverse effects of SD. These findings suggest that individual differences in inhibition-related cerebral activation after SD are influenced by chronotypes. In addition, ET individuals may be vulnerable to response inhibition. Thus, it is essential to take into consideration the chronotype in SD research and sleep medicine.