The temperature dependence of ultrasound-stimulated acoustic emission

Given the high variability of tissue properties during sonication, temperature monitoring is one of the most crucial components for accurate thermal treatment of tissues with focused ultrasound and other thermotherapy devices. Recently, the method of ultrasound-stimulated acoustic emission (USAE) has been introduced as a potential method for measurements of mechanical properties of tissues. In this paper, the dependence of USAE on tissue temperature is determined. Because USAE depends on the acoustic and mechanical properties, both of which vary with temperature, it is hypothesized that the USAE signal is also temperature-dependent and in such a way that it can be used to guide thermal therapy. In a series of experiments, ex vivo porcine muscle and fat samples were exposed to ultrasound at power levels that induce temperature elevation. In both tissue types, below the coagulation threshold, the USAE amplitude was found to vary linearly with temperature. However, at higher powers, the correlation with temperature was lost due mainly to the irreversible nature of the changes in the tissue properties. Theoretical simulations were used to interpret the USAE response change with temperature involving both reversible and irreversible changes and during both heating and cooling. These results indicate that USAE may have important promise as a potential method for localizing temperature elevation and, thus, thermal surgery monitoring, as well as detection of irreversible changes in tissues.     

An In Vivo,MRI-Integrated Real-Time Model of Active Contrast Extravasation in Acute Intracerebral Hemorrhage

BACKGROUND AND PURPOSE:The “spot sign” or contrast extravasation is strongly associated with hematoma formation and growth. An animal model of contrast extravasation is important to test existing and novel therapeutic interventions to inform present and future clinical studies. The purpose of this study was to create an animal model of contrast extravasation in acute intracerebral hemorrhage.MATERIALS AND METHODS:Twenty-eight hemispheres of Yorkshire male swine were insonated with an MR imaging–guided focused sonography system following lipid microsphere infusion and mean arterial pressure elevation. The rate of contrast leakage was quantified by using dynamic contrast-enhanced MR imaging and was classified as contrast extravasation or postcontrast leakage by using postcontrast T1. Hematoma volume was measured on gradient recalled-echo MR imaging performed 2 hours postprocedure. Following this procedure, sacrificed brain was subjected to histopathologic examination. Power level, burst length, and blood pressure elevation were correlated with leakage rate, hematoma size, and vessel abnormality extent.RESULTS:Median (intracerebral hemorrhage) contrast extravasation leakage was higher than postcontrast leakage (11.3; 6.3–23.2 versus 2.4; 1.1–3.1 mL/min/100 g; P < .001). Increasing burst length, gradient recalled-echo hematoma (ρ = 0.54; 95% CI, 0.2–0.8; P = .007), and permeability were correlated (ρ = 0.55; 95% CI, 0.1–0.8; P = .02). Median permeability (P = .02), gradient recalled-echo hematoma (P = .02), and dynamic contrast-enhanced volumes (P = .02) were greater at 1000 ms than at 10 ms. Within each burst-length subgroup, incremental contrast leakage was seen with mean arterial pressure elevation (ρ = 0.2–0.8).CONCLUSIONS:We describe a novel MR imaging–integrated real-time swine intracerebral hemorrhage model of acute hematoma growth and contrast extravasation.

Intracerebral hemorrhage (ICH) accounts for 10%–30% of strokes and is the most deadly and disabling stroke type with little improvement in mortality seen during the past 20 years.¹ These characteristics underscore the importance of developing a better understanding of the pathophysiology of ICH formation and growth to facilitate the development of improved therapeutic agents or interventions.² The causative lesion in primary ICH is yet to be elucidated, though pathologic studies demonstrate focal vessel integrity loss in association with blood extravasation into the brain parenchyma.³ Following initial ICH formation, continuous^4,5 or delayed⁶ extravasation results in hematoma expansion,⁷ which is associated with early neurologic deterioration and significant mortality.⁸Several recent studies have shown an association between contrast extravasation (CE) detected on CTA, coined the CTA “spot sign,” and hematoma growth.^9–14 Prospective studies have demonstrated that contrast extravasation independently predicts a larger hematoma size and a poorer clinical outcome.^13,14 These are the first clinical studies to suggest a robust “real-time” imaging marker of hematoma expansion. Three clinical studies are presently enrolling patients dichotomized by the CTA spot sign to validate the prior study findings and to determine the therapeutic efficacy of recombinant factor VIIa or tranexamic acid.^15–17 A more recent study using dynamic spot sign imaging with a biphasic CT perfusion protocol¹⁸ has confirmed 2 patterns of contrast extravasation associated with significantly different rates of leakage. These patterns, comprising a brisker active extravasation (spot sign) and slower postcontrast leakage (PCL),¹⁹ are also demonstrated with early and late structural imaging,^10,19 dynamic CTA/CTP,¹⁸ and biphasic or repeat delayed CTA acquisitions.¹²Morphologic patterns and more recent studies illustrate that the spot sign is not an all-or-none phenomenon but constitutes a spectrum of extravasation.^18,19 The extravasation rate likely significantly impacts timely and clinically meaningful hemostasis.²⁰ A bleeding threshold likely exists beyond which prothrombotic treatment is futile, exposing patients to harmful adverse effects without hope of therapeutic benefit.²¹ Increasingly, new innovative surgical techniques are being developed to address contrast extravasation.²² Knowledge of the impact of the extravasation rate on therapeutic response is critical to stratify patients to the most appropriate therapies. An animal model of acute contrast extravasation in ICH could potentially inform the patient-selection process. We describe a novel MR imaging–integrated real-time swine model of acute hematoma growth and contrast extravasation.     

Contrast-Enhanced Transcranial Two-Dimensional Ultrasound Imaging Using Shear-Mode Conversion at Low Frequency

The distortion and attenuation of transcranial ultrasound (US) signals are significant problems in US imaging of the brain. Of the variety of proposed solutions, shear-mode transmission through the skull is one of the more recent options and has been shown to reduce distortion of the US beam. This study examined the effects of transcranial shear-mode transmission on the images of a contrast-agent–filled polytetrafluoroethylene tube produced by a 32-element 750 kHz linear phased array transducer through an ex vivo human skull section. Although the tube was successfully imaged using shear-mode transmission with subharmonic imaging in 6 of 9 cases, the tube was visible in only 1 of 9 cases for both the fundamental and the second harmonic frequencies. Some improvement in the location of the axial image was seen at the fundamental frequency using shear mode. No improvement was seen at the other two frequencies, but this may be due to low transducer sensitivity. As well, neither the presence of the skull nor the incident angle changed the distance at which signals from the two tubes could be resolved. With this transducer, these distances were found to be 5 mm laterally and 3 mm axially for the fundamental and second harmonic images, and 10 mm and 5 mm for the subharmonic images. The results show that the subharmonic signal was the most successful of the three examined in penetrating a thick skull but that the success comes at the cost of image resolution.     

Heart rate variability in prediction of individual adaptation to endurance training in recreational endurance runners

The aim of this study was to investigate whether nocturnal heart rate variability (HRV) can be used to predict changes in endurance performance during 28 weeks of endurance training. The training was divided into 14 weeks of basic training (BTP) and 14 weeks of intensive training periods (ITP). Endurance performance characteristics, nocturnal HRV, and serum hormone concentrations were measured before and after both training periods in 28 recreational endurance runners. During the study peak treadmill running speed (V_peak) improved by 7.5±4.5%. No changes were observed in HRV indices after BTP, but after ITP, these indices increased significantly (HFP: 1.9%, P=0.026; TP: 1.7%, P=0.007). Significant correlations were observed between the change of V_peak and HRV indices (TP: r=0.75, P<0.001; HFP: r=0.71, P<0.001; LFP: r=0.69, P=0.01) at baseline during ITP. In order to lead to significant changes in HRV among recreational endurance runners, it seems that moderate‐ and high‐intensity training are needed. This study showed that recreational endurance runners with a high HRV at baseline improved their endurance running performance after ITP more than runners with low baseline HRV.     

Two-photon fluorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood�Cbrain barrier opening

Blood–brain barrier (BBB) disruption can be achieved with ultrasound (US) and circulating microbubble (MB) contrast agent. Using dorsal US sonication and Definity, an MB contrast agent, responses of the cortical cerebral vasculature to BBB opening were observed with varying acoustic peak negative pressure (0.071 to 0.25 MPa) under two-photon microscope. Wistar rats with a craniotomy were sonicated with a single piezoelectric transducer following the intravenous injection of Texas Red for visualization of vasculature and leakage from BBB opening. Based on time-dependent intensity change in the extravascular area, the leakage was classified into three types: fast, sustained, and slow. Fast leakage was characterized by a rapid increase to peak intensity during sonication, but a decrease afterwards, occurring at all pressures and vessels sizes analyzed in our study. Sustained leakage was indicated by a similar, immediate increase to peak intensity but one that remained elevated for the duration of imaging, occurring at low-to-intermediate pressures. Slow leakage began 5 to 15 minutes after sonication, dominating at low pressures, and was more prevalent among smaller vessels than fast and sustained leakage. Our study showed the possibility of controlling leakage type and vessel size in US-induced BBB opening through varying acoustic pressure.     

Randomized clinical trial comparing ambulatory and inpatient care after inguinal hernia repair in patients aged 65 years or older

Background

There is a lack of evidence from randomized studies of the feasibility of ambulatory surgery in patients aged 65 years and older.

Methods

Medically stable patients scheduled for open inguinal hernia repair, with postoperative care available at home, were randomized to receive treatment either as outpatients or inpatients. Younger patients undergoing the same procedure served as a reference group. Outcome measures during the 2 weeks after surgery were complications, unplanned admissions, visits to the hospital, unplanned visits to primary health care, and patients' acceptance of the type of provided care.

Results

Of 151 patients, 89 were included. Main reasons for exclusion were lack of postoperative company (16%), unwillingness to participate (13%), and medical conditions (10%). All outpatients were discharged home as planned, and none of the study patients were readmitted to the hospital. Patient satisfaction was high with no differences between the groups.

Conclusions

Ambulatory surgery was safe and well accepted by older, medically stable patients.     

A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels

Ultrasound contrast agents inside a microvessel, when driven by ultrasound, oscillate and induce mechanical stresses on the vessel wall. These mechanical stresses can produce beneficial therapeutic effects but also induce vessel rupture if the stresses are too high. Therefore, it is important to use sufficiently low pressure amplitudes to avoid rupturing the vessels while still inducing the desired therapeutic effects. In this work, we developed a comprehensive three-dimensional model of a confined microbubble inside a vessel while considering the bubble shell properties, blood viscosity, vessel wall curvature and the mechanical properties of the vessel wall. Two bubble models with the assumption of a spherical symmetric bubble and a simple asymmetrical bubble were simulated. This work was validated with previous experimental results and enabled us to evaluate the microbubbles' behaviour and the resulting mechanical stresses induced on the vessel walls. In this study, the fluid shear and circumferential stresses were evaluated as indicators of the mechanical stresses. The effects of acoustical parameters, vessel viscoelasticity and rigidity, vessel/bubble size and off-centre bubbles on bubble behaviour and stresses on the vessel were investigated. The fluid shear and circumferential stresses acting on the vessel varied with time and location. As the frequency changed, the microbubble oscillated with the highest amplitude at its resonance frequency which was different from the resonance frequency of an unbound bubble. The bubble resonance frequency increased as the rigidity of a flexible vessel increased. The fluid shear and circumferential stresses peaked at frequencies above the bubble's resonance frequency. The more rigid the vessels were, the more damped the bubble oscillations. The synergistic effect of acoustic frequency and vessel elasticity had also been investigated since the circumferential stress showed either an increasing trend or a decreasing one versus the vessel rigidity at different acoustic frequencies. When the acoustic pressure was increased from 52 to 680 kPa, the maximum bubble radius increase by 2.5 fold, and the maximum shear and circumferential stress increased by 15.7 and 18.3 fold, respectively. The shear stress was largest when the acoustic frequency was higher (3.25 MHz) and the ratio of the vessel radius to the bubble radius was lower. The circumferential stress was largest when the bubble wall was closer to the vessel wall. An oscillating off-centre bubble forms a mushroom shape with the most damping on the points closest to the vessel wall.     

The design of a focused ultrasound transducer array for the treatment of stroke: a simulation study

High intensity focused ultrasound (HIFU) is capable of mechanically disintegrating blood clots at high pressures. Safe thrombolysis may require frequencies higher than those currently utilized by transcranial HIFU. Since the attenuation and focal distortion of ultrasound in bone increases at higher frequencies, resulting focal pressures are diminished. This study investigated the feasibility of using transcranial HIFU for the non-invasive treatment of ischemic stroke. The use of large aperture, 1.1-1.5 MHz phased arrays in targeting four clinically relevant vessel locations was simulated. Resulting focal sizes decreased with frequency, producing a maximum -3 dB depth of field and lateral width of 2.0 and 1.2 mm, respectively. Mean focal gains above an order of magnitude were observed in three of four targets and transducer intensities required to achieve thrombolysis were determined. Required transducer element counts are about an order of magnitude higher than what currently exists and so, although technically feasible, new arrays would need to be developed to realize this as a treatment modality for stroke.     

Study of factors affecting the magnitude and nature of ultrasound exposure with in vitro set-ups

Therapeutic ultrasound is a clinically applied method to improve fracture healing and holds great potential as a manipulator of biologic material relevant to tissue engineering approaches. Unfortunately, the cell stimulating property of ultrasound is not known, which inhibits the optimal use of this technique. Additionally, many in vitro studies in this field use ultrasound configurations that are vulnerable to errors during calibration and use. These errors arise from the structural simplicity and incomplete characterization of these configurations. In this study, pulse-echo ultrasound, laser Doppler vibrometry and Schlieren imaging were applied to noninvasively characterize common in vitro experimental configurations. Fine wire thermocouple measurements were conducted to characterize any possible temperature rise during the ultrasound exposures. The results quantified the frequency dependent sound transmission through culture wells and the standing wave effect within the cell volume. These effects can cause uncertainty of up to 700% in the actual ultrasound exposure experienced by the cell. A temperature rise of 2.7°C was measured from an ultrasound configuration commonly used in vitro ultrasound studies. Furthermore, wave mode conversion in culture wells was observed, emphasizing the complexity of these sonications. Similar type Lamb waves have been observed in bone in vivo. Thus, Lamb waves may be a mechanism for stimulating the cells.     

Investigation of optimal method for inducing harmonic motion in tissue using a linear ultrasound phased array--a simulation study

Many noninvasive ultrasound techniques have been developed to explore mechanical properties of soft tissues. One of these methods, Localized Harmonic Motion Imaging (LHMI), has been proposed to be used for ultrasound surgery monitoring. In LHMI, dynamic ultrasound radiation-force stimulation induces displacements in a target that can be measured using pulse-echo imaging and used to estimate the elastic properties of the target. In this initial, simulation study, the use of a one-dimensional phased array is explored for the induction of the tissue motion. The study compares three different dual-frequency and amplitude-modulated single-frequency methods for the inducing tissue motion. Simulations were computed in a homogeneous soft-tissue volume. The Rayleigh integral was used in the simulations of the ultrasound fields and the tissue displacements were computed using a finite-element method (FEM). The simulations showed that amplitude-modulated sonication using a single frequency produced the largest vibration amplitude of the target tissue. These simulations demonstrate that the properties of the tissue motion are highly dependent on the sonication method and that it is important to consider the full three-dimensional distribution of the ultrasound field for controlling the induction of tissue motion.