Demonstration of enhanced temperature elevation due to nonlinear propagation of focussed ultrasound in dog's thigh in vivo

The results of an experimental study quantifying the temperature elevation gains produced by nonlinear propagation of focussed ultrasound fields in dogs' thighs in vivo are presented. Also, the intensity dependence of power absorption from a focussed ultrasound field was studied. The absorbed power appeared to elevate above intensities of 150-250 W cm-2 at 1 MHz in vivo. Enhanced temperature elevations were demonstrated at the same intensity levels, with the size of the elevation increasing with intensity. This phenomenon was large enough to be useful during focussed ultrasound hyperthermia since the maximum temperature gain was about 2 degrees C when a 5 degrees C temperature elevation was induced in the tissue. Using multiple overlapping beams, this effect was further increased.     

Theoretical design of a spherically sectioned phased array for ultrasound surgery of the liver.

GOAL: The theoretical explanation of the limits of an array transducer to coagulate large tissues volumes. METHODS: A theoretical model is used to illustrate the focal limitations of a spherically sectioned array designed for the treatment of deep seated tissue, e.g. liver. The design optimizes the acoustic dose as a function of the focal depth and available acoustic aperture with the goal of coagulating large volumes in a single sonication period. A quantitative measure of the possible region of focal necrosis is modeled as a function of array parameters with the limiting criteria being near field heating and patient pain. RESULTS: Acoustic simulations show that the maximum distance to produce continuous necrosis between foci in a multiple focus pattern and in a temporally multiplexed pattern is approximately 50% larger than the distance needed between sequential foci. CONCLUSION: Multiple focus patterns or rapidly scanned single foci are significantly advantageous to sequential sonications of a single focus transducer.     

Influence of crystallinity on the thermoelectric power factor of P3HT vapour-doped with F4TCNQ

Doping of the conjugated polymer poly(3-hexylthiophene) (P3HT) with the p-dopant 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) is a widely used model system for organic thermoelectrics. We here study how the crystalline order influences the Seebeck coefficient of P3HT films doped with F4TCNQ from the vapour phase, which leads to a similar number of F4TCNQ anions and hence (bound + mobile) charge carriers of about 2 × 10⁻⁴ mol cm⁻³. We find that the Seebeck coefficient first slightly increases with the degree of order, but then again decreases for the most crystalline P3HT films. We assign this behaviour to the introduction of new states in the bandgap due to planarisation of polymer chains, and an increase in the number of mobile charge carriers, respectively. Overall, the Seebeck coefficient varies between about 40 to 60 μV K⁻¹. In contrast, the electrical conductivity steadily increases with the degree of order, reaching a value of more than 10 S cm⁻¹, which we explain with the pronounced influence of the semi-crystalline nanostructure on the charge-carrier mobility. Overall, the thermoelectric power factor of F4TCNQ vapour-doped P3HT increases by one order of magnitude, and adopts a value of about 3 μW m⁻¹ K⁻² in the case of the highest degree of crystalline order.

The crystallinity of P3HT strongly benefits the electrical conductivity but not Seebeck coefficient, leading to an increase in power factor by one order of magnitude.     

The incidence of stress symptoms and heart rate variability during sleep and orthostatic test

This study examined the relation of self-reported stress to cardiac autonomic modulation in real-life conditions. The participants for the study were healthy male (N = 59) and female (N = 40) employees (age 40 ± 10 years). A single-item question and a 14-item questionnaire on perceived stress were administered to the participants before the experimental night. RR-intervals (RRI) were recorded during night sleep and an orthostatic test after awakening at home. The RRI data were analyzed for heart rate (HR) and heart rate variability (HRV) in time and frequency domains. Nocturnal urinary stress hormone (cortisol, adrenal and noradrenal) secretion was also analyzed. Based on the self-reported stress, the participants were divided into either low or high stress group. The results showed that higher incidence of stress symptoms was significantly associated with lower HRV in the orthostatic test regardless of age and gender. Differences between the stress groups in HRV indices were approximately 20–50 and 30–75% in supine and standing positions, respectively. No difference was found in nocturnal HR, HRV, or stress hormone secretion between the stress groups. Higher incidence of stress symptoms was significantly associated with greater decrease of HRV from night sleep to the orthostatic test, as a response to awakening. In conclusion, the present findings support the view that autonomic modulation measured in the orthostatic test, but not during night sleep, is related to self-reported stress.     

MRI-guided gas bubble enhanced ultrasound heating in in vivo rabbit thigh

In this study, we propose a focused ultrasound surgery protocol that induces and then uses gas bubbles at the focus to enhance the ultrasound absorption and ultimately create larger lesions in vivo. MRI and ultrasound visualization and monitoring methods for this heating method are also investigated. Larger lesions created with a carefully monitored single ultrasound exposure could greatly improve the speed of tumour coagulation with focused ultrasound. All experiments were performed under MRI (clinical, 1.5 T) guidance with one of two eight-sector, spherically curved piezoelectric transducers. The transducer, either a 1.1 or 1.7 MHz array, was driven by a multi-channel RF driving system. The transducer was mounted in an MRI-compatible manual positioning system and the rabbit was situated on top of the system. An ultrasound detector ring was fixed with the therapy transducer to monitor gas bubble activity during treatment. Focused ultrasound surgery exposures were delivered to the thighs of seven New Zealand while rabbits. The experimental, gas-bubble-enhanced heating exposures consisted of a high amplitude 300 acoustic watt, half second pulse followed by a 7 W, 14 W or 21 W continuous wave exposure for 19.5 s. The respective control sonications were 20 s exposures of 14 W, 21 W and 28 W. During the exposures, MR thermometry was obtained from the temperature dependency of the proton resonance frequency shift. MRT2-enhanced imaging was used to evaluate the resulting lesions. Specific metrics were used to evaluate the differences between the gas-bubble-enhanced exposures and their respective control sonications: temperatures with respect to time and space, lesion size and shape, and their agreement with thermal dose predictions. The bubble-enhanced exposures showed a faster temperature rise within the first 4 s and higher overall temperatures than the sonications without bubble formation. The spatial temperature maps and the thermal dose maps derived from the MRI thermometry closely correlated with the resulting lesion as examined by T2-weighted imaging. The lesions created with the gas-bubble-enhanced heating exposures were 2-3 times larger by volume, consistently more spherical in shape and closer to the transducer than the control exposures. The study demonstrates that gas bubbles can reliably be used to create significantly larger lesions in vivo. MRI thermometry techniques were successfully used to monitor the thermal effects mediated by the bubble-enhanced exposures.     

Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity

Acoustic emission was monitored during focused ultrasound exposures in conjunction with an ultrasound contrast agent (Optison) in order to determine if cavitation activity is associated with the induction of blood-brain barrier disruption (BBBD). Thirty-four locations were sonicated (frequency: 260 kHz) at targets 10 mm deep in rabbit brain (N = 9). The sonications were applied at peak pressure amplitudes ranging from 0.11 to 0.57 MPa (burst length: 10 ms; repetition frequency of 1 Hz; duration: 20 s). Acoustic emission was recorded with a focused passive cavitation detector. This emission was recorded at each location during sonications with and without Optison. Detectable wideband acoustic emission was observed only at 0.40 and 0.57 MPa. BBBD was observed in contrast MRI after sonication at 0.29-0.57 MPa. The appearance of small regions of extravasated erythrocytes appeared to be associated with this wideband emission signal. The results thus suggest that BBBD resulting from focused ultrasound pulses in the presence of Optison can occur without indicators for inertial cavitation in vivo, wideband emission and extravasation. If inertial cavitation is not responsible for the BBBD, other ultrasound/microbubble interactions are likely the source. A significant increase in the emission signal due to Optison at the second and third harmonics of the ultrasound driving frequency was found to correlate with BBBD and might be useful as an online method to indicate when the disruption occurs.     

Local frequency dependence in transcranial ultrasound transmission

The development of large-aperture multiple-source transducer arrays for ultrasound transmission through the human skull has demonstrated the possibility of controlled and substantial acoustic energy delivery into the brain parenchyma without the necessitation of a craniotomy. The individual control of acoustic parameters from each ultrasound source allows for the correction of distortions arising from transmission through the skull bone and also opens up the possibility for electronic steering of the acoustic focus within the brain. In addition, the capability to adjust the frequency of insonation at different locations on the skull can have an effect on ultrasound transmission. To determine the efficacy and applicability of a multiple-frequency approach with such a device, this study examined the frequency dependence of ultrasound transmission in the range of 0.6-1.4 MHz through a series of 17 points on four ex vivo human skulls. Effects beyond those that are characteristic of frequency-dependent attenuation were examined. Using broadband pulses, it was shown that the reflected spectra from the skull revealed information regarding ultrasound transmission at specific frequencies. A multiple-frequency insonation with optimized frequencies over the entirety of five skull specimens was found to yield on average a temporally brief 230% increase in the transmitted intensity with an 88% decrease in time-averaged intensity transmission within the focal volume. This finding demonstrates a potential applicability of a multiple-frequency approach in transcranial ultrasound transmission.     

500-element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls.

The aim of this study was to test a prototype MRI-compatible focused ultrasound phased array system for trans-skull brain tissue ablation. Rabbit thigh muscle and brain were sonicated with a prototype, hemispherical 500-element ultrasound phased array operating at frequencies of 700-800 kHz. An ex vivo human skull sample was placed between the array and the animal tissue. The temperature elevation during 20-30-sec sonications was monitored using MRI thermometry. The induced focal lesions were observed in T2 and contrast-enhanced T1-weighted fast spin echo images. Whole brain histology evaluation was performed after the sonications. The results showed that sharp temperature elevations can be produced both in the thigh muscle and in the brain. High-power sonications (600-1080 W) produced peak temperatures up to 55 degrees C and focal lesions that were consistent with thermal tissue damage. The lesion size was found to increase with increasing peak temperature. The device was then modified to operate in the orientation that will be used in the clinic and successfully tested in phantom experiments. As a conclusion, this study demonstrates that it is possible to create ultrasound-induced lesions in vivo through a human skull under MRI guidance with this large-scale phased array.     

Magnetic resonance image-guided focused ultrasound surgery

The powerful union of focused ultrasound and magnetic resonance imaging (MRI) has created a new approach to noninvasive surgery. By using this integrated therapy delivery system, the physician can correctly localize tumors, optimally target acoustic energy, monitor energy deposition in real time, and accurately control the deposited thermal dose within the entire tumor volume. This satisfies the requirements for "ideal surgery." In a real sense, MRI provides the "road map" by which focused ultrasound surgery (FUS) is followed. The advantages of MRI over ultrasound guidance in controlling FUS lie in the more sensitive detection of tumor target, the real-time detection of tissue temperature, and the confirmation of thermally induced tissue changes-powerful features that eventually can replace the traditional surgical approach. Applying software that connects the therapy and imaging system (the "Dosimetry Workstation"), the physician can generate an entire treatment plan from quantifying temperature changes to positioning the therapy transducer. The noninvasive debulking of tumors without disturbing adjacent, functionally intact structures is thereby accomplished.