Neonatal EEG at scalp is focal and implies high skull conductivity in realistic neonatal head models.

The potential improvements in spatial resolution of neonatal EEG used in source localization have been challenged by the insufficiencies in realistic neonatal head models. Our present study aimed at using empirical methods to indirectly estimate skull conductivity; the model parameter that is known to significantly affect the behavior of newborn scalp EEG and cause it to be markedly different from that of an adult. To this end, we used 64 channel EEG recordings to study the spatial specificity of scalp EEG by assessing the spatial decays in focal transients using both amplitudes and between-c'hannels linear correlations. The findings showed that these amplitudes and correlations decay within few centimeters from the reference channel/electrode, and that the nature of the decay is independent of the scalp area. This decay in newborn infants was found to be approximately three times faster than the corresponding decay in adult EEG analyzed from a set of 256 channel recordings. We then generated realistic head models using both finite and boundary element methods along with a manually segmented magnetic resonance images to study the spatial decays of scalp potentials produced by single dipole in the cortex. By comparing the spatial decays due to real and simulated EEG for different skull conductivities (from 0.003 to 0.3S/m), we showed that a close match between the empirical and simulated decays was obtained when the selected skull conductivity for newborn was around 0.06-0.2S/m. This is over an order of magnitude higher than the currently used values in adult head modeling. The results also showed that the neonatal scalp EEG is less smeared than that of an adult and this characteristic is the same across the entire scalp, including the fontanel region. These results indicate that a focal cortical activity is generally only registered by electrodes within few centimeters from the source. Hence, the conventional 10 to 20 channel neonatal EEG acquisition systems give a significantly spatially under sampled scalp EEG and may, consequently, give distorted pictures of focal brain activities. Such spatial specificity can only be reconciled by appreciating the anatomy of the neonatal head, especially the still unossified skull structure that needs to be modeled with higher conductivities than conventionally used in the adults.

Spatial patterning of the neonatal EEG suggests a need for a high number of electrodes.

There is an increasing demand for source analysis of neonatal EEG, but currently there is inadequate knowledge about i) the spatial patterning of neonatal scalp EEG and hence ii) the number of electrodes needed to capture neonatal EEG in full spatial detail. This study addresses these issues by using a very high density (2.5mm interelectrode spacing) linear electrode array to assess the spatial power spectrum, by using a high density (64 electrodes) EEG cap to assess the spatial extent of the common oscillatory bouts in the neonatal EEG and by using a neonatal size spherical head model to assess the effects of source depth and skull conductivities on the spatial frequency spectrum. The linear array recordings show that the spatial power spectrum decays rapidly until about 0.5-0.8 cycles per centimeter. The dense array EEG recordings show that the amplitude of oscillatory events decays within 4-6 cm to the level of global background activity, and that the higher frequencies (12-20 Hz) show the most rapid spatial decline in amplitude. Simulation with spherical head model showed that realistic variation in skull conductivity and source depths can both introduce orders of magnitude difference in the spatial frequency of the scalp EEG. Calculation of spatial Nyquist frequencies from the spatial power spectra suggests that an interelectrode distance of about 6-10mm would suffice to capture the full spatial texture of the raw EEG signal at the neonatal scalp without spatial aliasing or under-sampling. The spatial decay of oscillatory events suggests that a full representation of their spatial characteristics requires an interelectrode distance of 10-20mm. The findings show that the conventional way of recording neonatal EEG with about 10 electrodes ignores most spatial EEG content, that increasing the electrode density is necessary to improve neonatal EEG source localization and information extraction, and that prospective source models will need to carefully consider the neonatally relevant ranges of tissue conductivities and source depths when source localizing cortical activity in neonates.

Modeling ultrasound propagation through material of increasing geometrical complexity.

Ultrasound is increasingly being recognized as a neuromodulatory and therapeutic tool, inducing a broad range of bio-effects in the tissue of experimental animals and humans. To achieve these effects in a predictable manner in the human brain, the thick cancellous skull presents a problem, causing attenuation. In order to overcome this challenge, as a first step, the acoustic properties of a set of simple bone-modeling resin samples that displayed an increasing geometrical complexity (increasing step sizes) were analyzed. Using two Non-Destructive Testing (NDT) transducers, we found that Wiener deconvolution predicted the Ultrasound Acoustic Response (UAR) and attenuation caused by the samples. However, whereas the UAR of samples with step sizes larger than the wavelength could be accurately estimated, the prediction was not accurate when the sample had a smaller step size. Furthermore, a Finite Element Analysis (FEA) performed in ANSYS determined that the scattering and refraction of sound waves was significantly higher in complex samples with smaller step sizes compared to simple samples with a larger step size. Together, this reveals an interaction of frequency and geometrical complexity in predicting the UAR and attenuation. These findings could in future be applied to poro-visco-elastic materials that better model the human skull.

Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions.

Rationale: Treating diseases of the brain such as Alzheimer's disease (AD) is challenging as the blood-brain barrier (BBB) effectively restricts access of a large number of potentially useful drugs. A potential solution to this problem is presented by therapeutic ultrasound, a novel treatment modality that can achieve transient BBB opening in species including rodents, facilitated by biologically inert microbubbles that are routinely used in a clinical setting for contrast enhancement. However, in translating rodent studies to the human brain, the presence of a thick cancellous skull that both absorbs and distorts ultrasound presents a challenge. A larger animal model that is more similar to humans is therefore required in order to establish a suitable protocol and to test devices. Here we investigated whether sheep provide such a model. Methods: In a stepwise manner, we used a total of 12 sheep to establish a sonication protocol using a spherically focused transducer. This was assisted by ex vivo simulations based on CT scans to establish suitable sonication parameters. BBB opening was assessed by Evans blue staining and a range of histological tests. Results: Here we demonstrate noninvasive microbubble-mediated BBB opening through the intact sheep skull. Our non-recovery protocol allowed for BBB opening at the base of the brain, and in areas relevant for AD, including the cortex and hippocampus. Linear time-shift invariant analysis and finite element analysis simulations were used to optimize the position of the transducer and to predict the acoustic pressure and location of the focus. Conclusion: Our study establishes sheep as a novel animal model for ultrasound-mediated BBB opening and highlights opportunities and challenges in using this model. Moreover, as sheep develop an AD-like pathology with aging, they represent a large animal model that could potentially complement the use of non-human primates.