Prehospital stroke diagnosis and treatment in ambulances and helicopters-a concept paper.

Stroke is the second common cause of death and the primary cause of early invalidity worldwide. Different from other diseases is the time sensitivity related to stroke. In case of an ischemic event occluding a brain artery, 2000000 neurons die every minute. Stroke diagnosis and treatment should be initiated at the earliest time point possible, preferably at the site or during patient transport. Portable ultrasound has been used for prehospital diagnosis for applications other than stroke, and its acceptance as a valuable diagnostic tool "in the field" is growing. The intrahospital use of transcranial ultrasound for stroke diagnosis has been described extensively in the literature. Beyond its diagnostic use, first clinical trials as well as numerous preclinical work demonstrate that ultrasound can be used to accelerate clot lysis (sonothrombolysis) in presence as well as in absence of tissue plasminogen activator. Hence, the use of transcranial ultrasound for diagnosis and possibly treatment of stroke bares the potential to add to current stroke care paradigms significantly. The purpose of this concept article is to describe the opportunities presented by recent advances in transcranial ultrasound to diagnose and potentially treat large vessel embolic stroke in the prehospital environment.

Mechanical clot damage from cavitation during sonothrombolysis.

Recent studies have shown that high intensity focused ultrasound (HIFU) accelerates thrombolysis for ischemic stroke. Although the mechanisms are not fully understood, cavitation is thought to play an important role. The goal of this paper is to investigate the potential for cavitation to cause mechanical damage to a blood clot. The amount of damage to the fiber network caused by a single bubble expansion and collapse is estimated by two independent approaches: One based on the stretch of individual fibers and the other based on the energy available to break individual fibers. The two methods yield consistent results. The energy method is extended to the more important scenario of a bubble outside a blood clot that collapses asymmetrically creating an impinging jet. This leads to significantly more damage compared to a bubble embedded within the clot structure. Finally, as an example of how one can apply the theory, a simulation of the propagation of HIFU waves through model calvaria of varying density is explored. The maximum amount of energy available to cause damage to a blood clot increases as the density of the calvaria decreases.

Development of the mouse cochlea database (MCD).

The mouse cochlea database (MCD) provides an interactive, image database of the mouse cochlea for learning its anatomy and data mining of its resources. The MCD website is hosted on a centrally maintained, high-speed server at the following URL: (http://mousecochlea.umn.edu). The MCD contains two types of image resources, serial 2D image stacks and 3D reconstructions of cochlear structures. Complete image stacks of the cochlea from two different mouse strains were obtained using orthogonal plane fluorescence optical microscopy (OPFOS). 2D images of the cochlea are presented on the MCD website as: viewable images within a stack, 2D atlas of the cochlea, orthogonal sections, and direct volume renderings combined with isosurface reconstructions. In order to assess cochlear structures quantitatively, "true" cross-sections of the scala media along the length of the basilar membrane were generated by virtual resectioning of a cochlea orthogonal to a cochlear structure, such as the centroid of the basilar membrane or the scala media. 3D images are presented on the MCD website as: direct volume renderings, movies, interactive QuickTime VRs, flythrough, and isosurface 3D reconstructions of different cochlear structures. 3D computer models can also be used for solid model fabrication by rapid prototyping and models from different cochleas can be combined to produce an average 3D model. The MCD is the first comprehensive image resource on the mouse cochlea and is a new paradigm for understanding the anatomy of the cochlea, and establishing morphometric parameters of cochlear structures in normal and mutant mice.

In vitro evaluation of dual mode ultrasonic thrombolysis method for transcranial application with an occlusive thrombosis model.

A recent clinical trial of transcranial low-frequency ultrasound-mediated tPA thrombolysis (LFUT) showed cerebral hemorrhages associated with high spatial peak pulse average intensity (I(SPPA)), wide beam and long pulse duration. We developed an alternative approach to LFUT wherein diagnostic power M-mode Doppler (PMD) ultrasound is combined with LFUT, with a goal of increased safety. The effectiveness of such a dual mode ultrasonic thrombolysis (DMUT) was explored in vitro. The DMUT system emitted PMD (2 MHz) and LFUT (550 kHz) beams in alternating fashion from a small 12 mm diameter probe. The LFUT had a low I(SPPA) (2 W/cm(2)) and a short pulse duration (55 micros). Occlusive clots made in plastic tips from bovine plasma and thrombin were placed in flow models pressurized to 800 mH(2)O, with 600 IU/mL monteplase injected upstream. Recanalization times were then compared among three groups: the control (monteplase alone), PMD (monteplase + PMD) and DMUT (monteplase + PMD + LFUT). The capability of the DMUT device to monitor recanalization was demonstrated by observing with Doppler the degree of flow of a blood-mimicking fluid in the vicinity of the clot. Recanalization times were 37.9 +/- 22.9, 38.9 +/- 12.4 and 18.5 +/- 8.0 min, respectively, for the control, PMD and DMUT. There were significant differences between DMUT and the control (p = 0.0004) and between DMUT and PMD (p = 0.0004). Recanalization flows were clearly detected. It is anticipated that this DMUT method presents a safer and more efficient approach than normal LFUT.

In vivo estimates of the position of advanced bionics electrode arrays in the human cochlea.

OBJECTIVES: A new technique for determining the position of each electrode in the cochlea is described and applied to spiral computed tomography data from 15 patients implanted with Advanced Bionics HiFocus I, Ij, or Helix arrays. METHODS: ANALYZE imaging software was used to register 3-dimensional image volumes from patients' preoperative and postoperative scans and from a single body donor whose unimplanted ears were scanned clinically, with micro computed tomography and with orthogonal-plane fluorescence optical sectioning (OPFOS) microscopy. By use of this registration, we compared the atlas of OPFOS images of soft tissue within the body donor's cochlea with the bone and fluid/ tissue boundary available in patient scan data to choose the midmodiolar axis position and judge the electrode position in the scala tympani or scala vestibuli, including the distance to the medial and lateral scalar walls. The angular rotation 0 degrees start point is a line joining the midmodiolar axis and the middle of the cochlear canal entry from the vestibule. RESULTS: The group mean array insertion depth was 477 degrees (range, 286 degrees to 655 degrees). The word scores were negatively correlated (r = -0.59; p = .028) with the number of electrodes in the scala vestibuli. CONCLUSIONS: Although the individual variability in all measures was large, repeated patterns of suboptimal electrode placement were observed across subjects, underscoring the applicability of this technique.

Transcranial Near-Infrared Laser Transmission (NILT) Profiles (800 nm): Systematic Comparison in Four Common Research Species.

BACKGROUND AND PURPOSE: Transcranial near-infrared laser therapy (TLT) is a promising and novel method to promote neuroprotection and clinical improvement in both acute and chronic neurodegenerative diseases such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and Alzheimer's disease (AD) patients based upon efficacy in translational animal models. However, there is limited information in the peer-reviewed literature pertaining to transcranial near-infrared laser transmission (NILT) profiles in various species. Thus, in the present study we systematically evaluated NILT characteristics through the skull of 4 different species: mouse, rat, rabbit and human. RESULTS: Using dehydrated skulls from 3 animal species, using a wavelength of 800nm and a surface power density of 700 mW/cm2, NILT decreased from 40.10% (mouse) to 21.24% (rat) to 11.36% (rabbit) as skull thickness measured at bregma increased from 0.44 mm in mouse to 0.83 mm in rat and then 2.11 mm in rabbit. NILT also significantly increased (p<0.05) when animal skulls were hydrated (i.e. compared to dehydrated); but there was no measurable change in thickness due to hydration. In human calvaria, where mean thickness ranged from 7.19 mm at bregma to 5.91 mm in the parietal skull, only 4.18% and 4.24% of applied near-infrared light was transmitted through the skull. There was a slight (9.2-13.4%), but insignificant effect of hydration state on NILT transmission of human skulls, but there was a significant positive correlation between NILT and thickness at bregma and parietal skull, in both hydrated and dehydrated states. CONCLUSION: This is the first systematic study to demonstrate differential NILT through the skulls of 4 different species; with an inverse relationship between NILT and skull thickness. With animal skulls, transmission profiles are dependent upon the hydration state of the skull, with significantly greater penetration through hydrated skulls compared to dehydrated skulls. Using human skulls, we demonstrate a significant correlation between thickness and penetration, but there was no correlation with skull density. The results suggest that TLT should be optimized in animals using novel approaches incorporating human skull characteristics, because of significant variance of NILT profiles directly related to skull thickness.

Imaging the intact guinea pig tympanic bulla by orthogonal-plane fluorescence optical sectioning microscopy.

Orthogonal-plane fluorescence optical sectioning (OPFOS) microscopy was developed for the purpose of making quantitative measurements of the intact mammalian cochlea and to facilitate 3D reconstructions of complex features. A new version of this imaging apparatus was built with a specimen chamber designed to accommodate samples as large as the intact guinea pig bulla. This method left the cochlear connections with the vestibular system and with the ossicles of the middle ear undisturbed, providing views within the cochlea with no breaches of its structural integrity. Since the features within the bulla were not physically touched during the preparation process, the risk of damage was minimized, and were imaged in relatively pristine condition with spatial resolution to 16 microm. A description of the imaging method and specimen preparation procedure is presented, as are images of features from the cochlea, ossicles, and vestibular system.

Parametric mapping and quantitative analysis of the human calvarium.

In this paper we report how thickness and density vary over the calvarium region of a collection of human skulls. Most previous reports involved a limited number of skulls, with a limited number of measurement sites per skull, so data in the literature are sparse. We collected computer tomography (CT) scans of 51 ex vivo human calvaria, and analyzed these in silico using over 2000 measurement sites per skull. Thickness and density were calculated at these sites, for the three skull layers separately and combined, and were mapped parametrically onto the skull surfaces to examine the spatial variations per skull. These were found to be highly variable, and unique descriptors of the individual skulls. Of the three skull layers, the thickness of the inner cortical layer was found to be the most variable, while the least variable was the outer cortical density.

Effects of varying duty cycle and pulse width on high-intensity focused ultrasound (HIFU)-induced transcranial thrombolysis.

The goal was to test the effects of various combinations of pulse widths (PW) and duty cycles (DC) on high-intensity focused ultrasound (HIFU)-induced sonothrombolysis efficacy using an in vitro flow model. An ExAblate™ 4000 HIFU headsystem (InSightec, Inc., Israel) was used. Artificial blood clots were placed into test tubes inside a human calvarium and exposed to pulsatile flow. Four different duty cycles were tested against four different pulse widths. For all study groups, an increase in thrombolysis efficacy could be seen in association with increasing DC and/or PW (p < 0.0001). Using transcranial HIFU, significant thrombolysis can be achieved within seconds and without the use of lytic drugs in vitro. Longer duty cycles in combination with longer pulse widths seem to have the highest potential to optimize clot lysis efficacy.

Transcranial sonothrombolysis using high-intensity focused ultrasound: impact of increasing output power on clot fragmentation.

BACKGROUND: The primary goal of this study was to investigate the relationship between increasing output power levels and clot fragmentation during high-intensity focused ultrasound (HIFU)-induced thrombolysis. METHODS: A HIFU headsystem, designed for brain applications in humans, was used for this project. A human calvarium was mounted inside the water-filled hemispheric transducer. Artificial thrombi were placed inside the skull and located at the natural focus point of the transducer. Clots were exposed to a range of acoustic output power levels from 0 to 400 W. The other HIFU operating parameters remained constant. To assess clot fragmentation, three filters of different mesh pore sizes were used. To assess sonothrombolysis efficacy, the clot weight loss was measured. RESULTS: No evidence of increasing clot fragmentation was found with increasing acoustic intensities in the majority of the study groups of less than 400 W. Increasing clot lysis could be observed with increasing acoustic output powers. CONCLUSION: Transcranial sonothrombolysis could be achieved in vitro within seconds in the absence of tPA and without producing relevant clot fragmentation, using acoustic output powers of <400 W.

Introduction of a rabbit carotid artery model for sonothrombolysis research.

The goal of this study was to develop an in vivo sonothrombolysis model for stroke research. The rabbit carotid artery has average vessel diameters similar to human M1/M2 segments and allows generation of a thrombotic occlusion using various kinds of thrombus material as well as thrombus placement under visual control. It further allows real-time monitoring of flow and clot mechanics during the sonothrombolysis procedure using high-frequency diagnostic ultrasound. In the present study, the model will be introduced and first results to show feasibility using diagnostic as well as high-intensity focused ultrasound will be presented.