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In vitro fertilisation after stimulation of the ovulatory cycle has led to successful pregnancy. If more oocytes are recovered than are needed they may be left unfertilised, preserved, or donated to a recipient couple from whom oocytes cannot be obtained. A case of human pregnancy initiated by transfer of a donated embryo fertilised in vitro is reported. The donor was a 42 year old woman with primary infertility from whom six follicles were aspirated after stimulation of the ovulatory cycle. The recipient was a 38 year old infertile woman who had undergone several unsuccessful attempts for artificial insemination from a donor. Five oocytes were recovered from the donor's six follicles, four of which were inseminated with spermatozoa of the donor's husband and the fifth with a frozen sample of semen. Three of the four embryos fertilised by her husband were returned to the donor and the fifth was transferred to the recipient. No pregnancy was recorded in the donor, but pregnancy was confirmed in the recipient, though spontaneous abortion occurred after 10 weeks. This case will give useful information for further study of in vitro fertilisation, but also raises many ethical issues.

Focused ultrasound (FUS) neuromodulation has shown that mechanical waves can interact with cell membranes and mechanosensitive ion channels, causing changes in neuronal activity. However, the thorough understanding of the mechanisms involved in these interactions are hindered by different experimental conditions for a variety of animal scales and models. While the lack of complete understanding of FUS neuromodulation mechanisms does not impede benefiting from the current known advantages and potential of this technique, a precise characterization of its mechanisms of action and their dependence on experimental setup (e.g., tuning acoustic parameters and characterizing safety ranges) has the potential to exponentially improve its efficacy as well as spatial and functional selectivity. This could potentially reach the cell type specificity typical of other, more invasive techniques, e.g., opto-and chemogenetics or at least orientation-specific selectivity afforded by transcranial magnetic stimulation. Here, the mechanisms and their potential overlap are reviewed along with discussions on the potential insights into mechanisms that magnetic resonance imaging sequences along with a multimodal stimulation approach involving electrical, magnetic, chemical, light, and mechanical stimuli can provide.

Low-intensity focused ultrasound (FUS), combined with microbubbles, is able to locally, and noninvasively, open the blood-brain barrier (BBB), allowing nanoparticles to enter the brain. We present here a study on the diffusion process of gadolinium-based MRI contrast agents within the brain extracellular space after ultrasound-induced BBB permeabilization. Three compounds were tested (MultiHance, Gadovist, and Dotarem). We characterized their diffusion through in vivo experimental tests supported by theoretical models. Specifically, by estimation of the free diffusion coefficients from in vitro studies and of apparent diffusion coefficients from in vivo experiments, we have assessed tortuosity in the right striatum of 9 Sprague Dawley rats through a model correctly describing both vascular permeability as a function of time and diffusion processes occurring in the brain tissue. This model takes into account acoustic pressure, particle size, blood pharmacokinetics, and diffusion rates. Our model is able to fully predict the result of a FUS-induced BBB opening experiment at long space and time scales. Recovered values of tortuosity are in agreement with the literature and demonstrate that our improved model allows us to assess that the chosen permeabilization protocol preserves the integrity of the brain tissue.

The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies. The new generation of sono-sensitive agents, such as liquid-core droplets, can also potentially disrupt the blood-brain barrier after their ultrasound-induced vaporization. In this review, we describe the different compositions of agents used for ultrasound-mediated blood-brain barrier opening in recent studies, and we discuss the challenges of the past five years related to the optimal formulation of agents.

Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain. the real-time control of the ultrasound dose delivered through the skull is necessary as the range of pressure for efficient and safe BBB opening is very narrow. passive cavitation detection (pcD) is a method proposed to monitor the microbubble activity during ultrasound exposure. However, there is still no consensus on a reliable safety indicator able to predict potential damage in the brain. current approaches for the control of the beam intensity based on PCD employ a full-pulse analysis and may suffer from a lack of sensitivity and poor reaction time. To overcome these limitations, we propose an intra-pulse analysis to monitor the evolution of the frequency content during ultrasound bursts. We hypothesized that the destabilization of microbubbles exposed to a critical level of ultrasound would result in the instantaneous generation of subharmonic and ultra-harmonic components. This specific signature was exploited to define a new sensitive indicator of the safety of the ultrasound protocol. the approach was validated in vivo in rats and nonhuman primates using a retrospective analysis. our results demonstrate that intra-pulse monitoring was able to exhibit a sudden appearance of ultra-harmonics during the ultrasound excitation pulse. the repeated detection of such a signature within the excitation pulse was highly correlated with the occurrence of side effects such as hemorrhage and edema. Keeping the acoustic pressure at levels where no such sign of microbubble destabilization occurred resulted in safe BBB openings, as shown by MR images and gross pathology. this new indicator should be more sensitive than conventional full-pulse analysis and can be used to distinguish between potentially harmful and safe ultrasound conditions in the brain with very short reaction time.

In multiple sclerosis, individual lesion-type patterns on magnetic resonance imaging might be valuable for predicting clinical outcome and monitoring treatment effects. Neuropathological and imaging studies consistently show that cortical lesions contribute to disease progression. The presence of chronic active white matter lesions harboring a paramagnetic rim on susceptibility-weighted magnetic resonance imaging has been also associated with an aggressive form of multiple sclerosis. It is, however, still uncertain how these two types of lesions relate to each other, or which one plays a greater role in disability progression. In this prospective, longitudinal study in 100 multiple sclerosis patients (74 relapsing-remitting, 26 secondary progressive), we used ultra-high field 7-Tesla T2* susceptibility imaging to characterize cortical and rim lesion presence and evolution. Clinical evaluations were obtained over a mean period of 3.2 years in 71 patients, 46 of which had a follow-up magnetic resonance imaging. At baseline, cortical and rim lesions were identified in 96% and 63% of patients respectively. Rim lesion prevalence was similar across disease stages. Patients with rim lesions had higher cortical and overall white matter lesion load than subjects without rim lesions (P = 0.018–0.05). Altogether, cortical lesions increased by both count and volume over time (P = 0.004), while rim lesions expanded their volume (P = 0.023) whilst lacking new rim lesions; rimless white matter lesions increased their count but decreased their volume (P = 0.006). We used a modern machine learning algorithm based on extreme gradient boosting techniques to assess the cumulative power as well as individual importance of cortical and rim lesion types in predicting disease stage and disability progression, alongside with more traditional imaging markers. The most influential imaging features that discriminated between multiple sclerosis stages (area under the curve±standard deviation = 0.82 ± 0.08) included as expected the normalized white matter and thalamic volume, white matter lesion volume, but also leukocortical lesion volume. Subarachnoid cerebrospinal fluid and leukocortical lesion volumes, along with rim lesion volume were the most important predictors of Expanded Disability Status Scale progression (area under the curve±standard deviation = 0.69 ± 0.12). Taken together, these results indicate that, while cortical lesions are extremely frequent in multiple sclerosis, rim lesion development occurs only in a subset of patients. Both, however, persists over time and relates to disease progression. Their combined assessment is needed to improve the ability of identifying multiple sclerosis patients at risk of progressing disease.

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