Biomedical subjects

Kullervo Hynynen

Publications and source records attributed to Kullervo Hynynen.

At least 55 records · Page 3Linked to original sources

PubMed2004

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.

Animals↗

PubMed2004

Optical monitoring of ultrasound-induced bioeffects in glass catfish.

This study is an investigation of the therapeutic ultrasound (US) effects on the blood vessels of optically transparent fish in vivo. Although many investigators have characterized cavitation in vivo using remote-sensing methods (i.e., measuring the acoustic emissions caused by oscillating bubbles) very few have made direct observations of cavitation-induced damage. Anesthetized glass catfish, which are optically transparent, was injected with the contrast agent, Optison, and then insonified at pressures that ranged from 0.5-10 MPa (peak negative pressures). Two focused transducers were used in these experiments to cover a frequency range of 0.7-3.3 MHz. Sonications were pulsed with pulse durations of 100, 10, 1, 0.1 and 0.01 ms and a pulse repetition frequency (PRF) of 1 Hz. The entire length of one sonication at a specific pressure level was 20 s. An inverted microscope combined with a digital camera and video monitor were used optically to monitor and record US interaction with the blood vessels in the tail of the anesthetized fish at 200x magnification. The effects of the burst sonication were analyzed visually at each pressure level. For the 1.091-MHz sonications, the first type of damage that occurred due to the US interaction was structural damage to the cartilage rods that comprise the tail of the fish, and was characterized by a disintegration of the lining of the rod. Damage to the rods occurred, starting at 3.5 MPa, 3.1 MPa, 4.1 MPa and 5.5 MPa for the 100-ms, 10-ms, 1-ms and 100-micros sonications, respectively. The formation of large gas bubbles was observed in the blood vessels of the fish at threshold values of 3.8 MPa, 3.8 MPa and 5.3 MPa, for the 100-ms, 10-ms and 1-ms sonications, respectively. Neither gas bubble formation nor hemorrhaging was observed during 100-micros sonications. Bubble formation was always accompanied by an increase of damage to the rods at the area surrounding the bubble. At 1.091 MHz, petechial hemorrhage thresholds were observed at 4.1 MPa, 4.1 MPa and 6.1 MPa, respectively, for the three pulse durations. The thresholds for damage were the lowest for the 0.747-MHz sonications: they were 2.6 MPa for damage to the rods, 3.7 MPa for gas bubble formation and 2.4 MPa for hemorrhaging.

Acoustics↗

PubMed2004

Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles.

Local blood-brain barrier (BBB) opening is an advantageous approach for targeted drug delivery to the brain. Recently, it has been shown that focused ultrasound (US) exposures (sonications), when applied in the presence of preformed gas bubbles, caused magnetic-resonance (MR) proven reversible opening of the BBB in targeted locations. The cellular mechanisms of such transient barrier disruption are largely unknown. We investigated US-induced changes in endothelial cell fine morphology that resulted in the BBB opening in rabbits. To obtain evidence for the passage of blood-borne macromolecules through the opened transvascular routes, an immunocytochemical procedure for endogenous immunoglobulinG (IgG) was performed, in addition to the routine electron microscopy. An increased number of vesicles and vacuoles, fenestration and channel formation, as well as opening of some tight junctions, were seen in capillaries after low-power (0.55 W) sonication. Immunosignals presented in some of the vesicles and vacuoles, in the cytoplasmic channels and, so rarely, in intercellular clefts; immunosignals could also be seen in neuropil around the blood vessels. Damage to the cellular ultrastructure was not seen in these areas. However, cell destruction and leakage of IgG through defects of the endothelial lining took place at 3 W sonications. The data reveals that several mechanisms of transcapillary passage are possible after such sonications: 1. transcytosis; 2. endothelial cell cytoplasmic openings--fenestration and channel formation; 3. opening of a part of tight junctions; and 4. free passage through the injured endothelium (with the higher power sonications). These findings could be considered in further development of the strategy for drug delivery to brain parenchyma.

Animals↗

PubMed2004

Noninvasive thermal ablation of hepatocellular carcinoma by using magnetic resonance imaging-guided focused ultrasound.

A number of minimally invasive methods have been tested for the thermal ablation of liver tumors as an alternative to surgical resection. The use of focused ultrasound transducers to ablate deep tumors offers the first completely noninvasive alternative to these techniques. By increasing the flexibility of this technology with modern phased-array transducer design and by combining it with magnetic resonance imaging for targeting and online guidance, a powerful tool results with the potential to offer treatment to a larger population of patients, to reduce trauma to the patient, and to reduce the cost of treatment. In this article, we review previous work with focused ultrasound in the liver and recent experimental results with magnetic resonance imaging guidance.

Carcinoma, Hepatocellular↗

PubMed2004

Patterns of thermal deposition in the skull during transcranial focused ultrasound surgery.

The induction of temperature elevation by focused ultrasound is a noninvasive surgical technique for destroying tissue. This technique has been used clinically in soft tissues such as liver, prostate and breast. It has long been desired to extend this technique to noninvasive treatment of brain tumors. Although the skull was once thought to be an unsurpassable barrier to focused ultrasound treatment, it has been shown that the distortion caused by the skull can be corrected to produce a useful intracranial focus. However, the attenuation experienced by the ultrasound in passing through cranial bone is large, and consequently the skull is subject to the deposition of acoustic energy as heat. The nature and extent of this heating process has been difficult to characterize empirically. It is practically difficult to implant a sufficient number of thermocouples to obtain detailed temperature data directly, and bone is an unsuitable medium in which to perform noninvasive thermometry using proton chemical shift magnetic resonance imaging. Furthermore, skull specimens used experimentally lack active blood perfusion of the skull and the overlying scalp. This paper describes the use of large-scale acoustic and thermal simulations to calculate the distribution of temperature within the skull and brain that can be expected to occur during therapeutically useful focused ultrasound sonications of the brain. The results demonstrate that standing waves may be formed within the skull during transcranial sonication leading to nonuniform skull heating. However, the results also show that these effects can be sufficiently controlled to allow therapeutic ultrasound to be focused in the cranial base region of the brain without causing thermal damage to the scalp, skull or outer surface of the brain.

Body Temperature↗

PubMed2004

Simulation study for thermal dose optimization in ultrasound surgery of the breast.

In this paper the previously published optimization algorithm for thermal dose optimization is tested with numerical simulations. The simulations concern the thermal dose optimization in ultrasound surgery of the breast. The optimization algorithm is extended by setting the inequality constraint approximations to temperature in healthy tissue as well as in tumor region. In addition, the simulations are accomplished in realistic 3D geometry with varying thermal parameters. Another topic of the paper is to show the potential of the hemispherical phased array applicator for ultrasound surgery of the breast. With such an applicator larger tissue volumes can be treated with shorter time as compared to single element transducers. In simulations the geometrical focus of the applicator was placed mechanically in the middle of the treatable region. The whole tumor region was then scanned electrically by changing the phase of the emitted wave from individual elements. The simulations indicate that a feasible treatment plan can be achieved. In simulated cases the desired thermal dose was achieved for tumors with diameter from 1.5 to 2.4 cm, depending on the position of tumor. The maximum temperature limitations of 45 degrees C in healthy region and 80 degrees C in tumor region can be maintained in all simulations.

Algorithms↗

PubMed2003

Feasibility of internally referenced brain temperature imaging with a metabolite signal.

The feasibility of using a metabolite signal as an internal reference for self-referenced temperature distribution measurement was examined. Line scan echo-planar spectroscopic imaging (LSEPSI) was applied to obtain quick multi-voxel spectroscopic measurements and to avoid possible spectral degradation from motion. Temperature distribution in a rabbit brain in vivo was successfully visualized by means of the chemical shift of water, which was measured by using naturally abundant (up to 10 mM) N-acetyl-aspartate (NAA) as the reference signal. Unlike the phase-mapping approach, this technique does not require a pixel-by-pixel subtraction. Therefore, in theory, it is more resistant to inter-scan motion or changes in susceptibility. The spatial and temporal resolutions of this technique are 1.5 cm3 and 4.5 min. A higher signal-to-noise ratio and optimization of the water and outer-volume suppression capabilities will be required to further enhance the temperature-mapping capabilities.

Animals↗

PubMed2003

MRI-guided focused ultrasound surgery in the brain: tests in a primate model.

MRI-guided focused ultrasound was tested in the brains of rhesus monkeys. Locations up to 4.8 cm deep were targeted. Focal heating was observed in all cases with MRI-derived temperature imaging. Subthreshold heating was observed at the focus when the ultrasound beam was targeted with low power sonications, and in the ultrasound beam path during high-power exposures. Lethal temperature values and histologically confirmed tissue damage were confined to the focal zone (e.g., not in the ultrasound beam path), except when the focus was close to the bone. In that case, damage to the neighboring brain tissue was observed. Focal lesions were observed on histological examination and, in some cases, in MR images acquired immediately after the ultrasound exposures. The capabilities demonstrated in this study will be of benefit for clinical ultrasound therapies in the brain.

Animals↗

PubMed2003

The use of ultrasound-stimulated acoustic emission in the monitoring of modulus changes with temperature.

It has been previously shown that the amplitude of the ultrasound-stimulated acoustic emission (USAE) signal is sensitive to tissue temperature and, therefore, can help detect it. Its amplitude, however, is sensitive to both acoustical and mechanical parameters, that at most frequencies have opposite effects due to temperature. In this paper, we explore the feasibility of using a frequency shift of the resonant peaks of the USAE signal for monitoring the tissue stiffness variation with temperature. In a numerical simulation, the variation of the frequency shift at different temperatures is shown. Then, in a series of experiments involving a gel phantom and porcine muscle tissue, the frequency shift variation is shown to follow the known stiffness changes due to temperature. It is also shown that this shift indicates reversible changes as well as the onset of thermal coagulative necrosis. The necrosis is marked by a monotonically increasing positive frequency shift. It was thus shown that the USAE spectrum peaks undergo a negative shift (or, downshift) when the stiffness decreases and a positive shift (or, upshift) when the stiffness increases. The experimental frequency shifted around a peak at 22.1-22.5 kHz within a range of -250 to 80 Hz and -200 to 250 Hz for the gel and muscle tissue for the temperatures of 25-70 and 30-70 degrees C, respectively. Simulation and ex vivo experimental results indicate that the USAE frequency shift method can help decouple the mechanical from the acoustical parameter dependence as well as detect the onset of thermal coagulative necrosis.

Acoustics↗

PubMed2003

The threshold for brain damage in rabbits induced by bursts of ultrasound in the presence of an ultrasound contrast agent (Optison).

The purpose of this study was to test the hypothesis that burst ultrasound (US) in the presence of a US contrast agent using parameters similar to those used in brain blood flow measurements causes tissue damage. The brains of 10 rabbits were sonicated in 3-8 locations with 1.5-MHz, 10- micro s bursts repeated at a frequency of 1 kHz at temporal peak acoustic pressure amplitudes ranging from 2 to 12.7 MPa. The total sonication time for each location was 20 s. Before each sonication, a bolus of US contrast agent was injected IV. Contrast-enhanced magnetic resonance (MR) images were obtained after the sonications to detect local enhancement in the brain. Whole brain histological evaluation was performed, and the sections were stained with hematoxylin and eosin (H and E), TUNEL, and vanadium acid fuchsin (VAF) staining to evaluate tissue effects, including apoptosis and ischemia. Both the magnetic resonance imaging (MRI) contrast enhancement and histology findings indicated that brain tissue damage was induced at a pressure amplitude level of 6.3 MPa. The damage included vascular wall damage, hemorrhage and, eventually, necrosis. Mild vascular damage was observed localized in a few microscopic tissue volumes in about half of the sonicated locations at all pressure values tested (down to 2 MPa). However, these sonications did not induce any detectable tissue effects, including ischemia or apoptosis. As a conclusion, the study showed that the US exposure levels currently used for blood flow measurements in brain are below the threshold of blood-brain barrier opening or brain tissue damage. However, one should be aware that brain damage can be induced if the exposure level is increased.

Albumins↗

PubMed2003

Localized harmonic motion imaging: theory, simulations and experiments.

Several techniques have been developed in an effort to estimate mechanical properties of tissues. These techniques typically estimate static or harmonic motion resulting from an externally or internally applied mechanical stimulus. In this paper, we discuss the advantages of utilizing a new technique that performs radiofrequency (RF) signal tracking to estimate the localized oscillatory motion resulting from the harmonic radiation force produced by two focused ultrasound (US) transducer elements with overlapping beams oscillating at distinct frequencies. Finite-element and Monte-Carlo simulations were performed to characterize the range of oscillatory displacements produced by a harmonic radiation force. In the experimental verification, three transducers were used: two single-element focused transducers and one lead zirconate-titanate (PZT) composite 16-element probe. Four agar gels were utilized to determine the effect of stiffness on the motion amplitude. Estimates of the displacement relative to the initial position (i.e., at the onset of the application of the radiation force) were obtained during the application of the radiation force that oscillated at frequencies ranging between 200 Hz and 800 Hz. In the simulations, the estimated oscillatory displacement spanned from -800 to 600 microm and the frequencies of excitation could easily be estimated from the temporal variation of the displacement. In addition, a frequency upshift (on the order of tens of Hz) was estimated with stiffness increase. Furthermore, an exponential decrease of the displacement amplitude with stiffness was observed at all frequencies investigated. An M-mode version to depict both the spatial and temporal variations of the locally induced displacement was used. In experiments with gels of different stiffness, the resulting amplitude of the harmonic displacement estimated oscillated at the same frequencies and ranged from -300 to 250 microm. An exponential decrease of the displacement amplitude with the gel stiffness was also observed. In tissue experiments, the results showed that the method is feasible in tissues and that focused US surgery (FUS) ablation can be detected. These preliminary results demonstrate the feasibility of imaging localized harmonic motion as induced by an oscillatory US radiation force. Due to the highly localized and harmonic nature of the estimated response, this technique may be proven to be highly suitable for simple and accurate estimation of the elastic modulus variation in tissues due to disease.

Agar↗

PubMed2003

Ultrasound-mediated cavitation thresholds of liquid perfluorocarbon droplets in vitro.

This study was undertaken to measure the ultrasound (US)-mediated cavitation threshold of microdroplets as a function of its content and US parameters (frequency, amplitude and burst length). Albumin-coated droplets were prepared with perfluoropropane, perfluorohexane or perfluoromethylcyclohexane contents. The filtered suspensions were diluted to 1:1000 (v) and compared with Optison. The formulations were injected into an acoustically transparent vessel and sonicated with a single focused transducer. The frequencies employed were 0.74, 1.1, 2.18 and 3.3 MHz and the burst length and acoustic pressure were varied. The inertial cavitation threshold for each experiment was monitored through passive acoustic detection. The formation of droplet emulsion of the perfluorocarbon increased the natural boiling point of the perfluorocarbon. However, perfluorocarbon droplets having contents with higher molecular weights and boiling points did not have detectably higher inertial cavitation thresholds and, thus, the droplets do not need to be in a superheated state to be cavitated by US bursts. Therefore, higher boiling point perfluorocarbons should be investigated for this purpose and may prove to be useful for both imaging and therapy. The inertial cavitation threshold of perfluorocarbon droplets increases with frequency, and was approximately 0.7 MPa at 0.74 MHz and 1.75 MPa at 3.3 MHz. Optison, already in a gaseous state, has the lowest cavitation threshold of all formulations studied. Results show that, for the frequencies tested, there is no dependence between inertial cavitation threshold and burst lengths between 20 and 100 ms. As a conclusion, the inertial cavitation threshold of albumin-coated microdroplets of several perfluorocarbons was determined in vitro. The results indicate that the physical properties of these droplets are such that they may be useful for localized US therapies.

Acoustics↗

PubMed2003

Modeling of anomalies due to hydrophones in continuous-wave ultrasound fields.

Needle and spot-poled membrane hydrophones using polyvinylidene fluoride (PVDF) sensors are widely used for characterization of biomedical ultrasound fields. It is known that, in measurements of continuous-wave (CW) fields, standing waves may be generated between the transducer and the hydrophone, distorting the field and possibly alternating the signal of the hydrophone. This study uses a three-dimensional, full-wave method to computationally simulate the distortion in the CW field caused by needle and membrane hydrophones. The physical model used in simulations is based on the linear time-harmonic wave equation, which therefore neglects the effects of nonlinear wave propagation. The significance of the distortion is examined by comparing fields emitted by 0.5-5.0 MHz planar circular transducers in the absence and presence of the hydrophones. In addition, the effect of the field distortions on the signal of the hydrophones is studied with simulated measurements. The simulations showed an observable standing wave pattern between the source and the needle hydrophone if the diameter of the needle was larger than a half of the wavelength. However, the standing waves had no clear effect on the signal of the hydrophone. The presence of membrane hydrophone in the CW field generated notable standing waves. Furthermore, the standing waves caused a periodic distortion to the signal of the membrane hydrophone.

Artifacts↗

PubMed2003

Forward planar projection through layered media.

A planar forward projection algorithm is combined with ray theory to describe longitudinal propagation through an arbitrary number of randomly oriented isotropic layers. This method first measures the space-time pressure field in a plane, then uses wavevector frequency-domain methods to project the field through layered media and to an arbitrary new plane, not necessarily parallel to the initial plane. The approach is valid for longitudinal propagation through liquid layers and in solids, such as soft tissues, that can be approximated as viscous liquids. The algorithm is verified by propagating the field from a 0.5 MHz planar transducer through a combination of rubber, plastic, and water layers. Hydrophone measurements indicate correlation between measured and simulated fields for angles below the longitudinal critical angles of the layered materials.

Acoustics↗

PubMed2003

MR imaging-guided focused ultrasound surgery of uterine leiomyomas: a feasibility study.

The feasibility and safety of magnetic resonance (MR) imaging-guided focused ultrasound surgery for uterine leiomyomas is reported. Sequential sonications were delivered to nine targets. Temperature-sensitive phase-difference MR imaging monitored the location of the focus and measured tissue temperature elevations, ensuring therapeutic dose. MR images and hysterectomy specimens were evaluated. Six leiomyomas received full therapeutic doses, and 98.5% of the sonications were visualized. MR thermometry was successful in all sonications and cases. Focal necrotic lesions were seen in all cases at MR, and five were pathologically confirmed. MR imaging-guided focused ultrasound causes thermocoagulation and necrosis in uterine leiomyomas and is feasible and safe, without serious consequences.

Adult↗

PubMed2003

Interlaboratory acoustic power measurement.

OBJECTIVE: This article describes an American Institute of Ultrasound in Medicine-sponsored intercomparison of the results of acoustic power measurements performed by several laboratories. METHODS: Two primary calibration techniques, namely, planar scanning and radiation force balance, were used in the frequency range typical of that in which sonographic imaging devices operate. The same reference source, the National Institute of Standards and Technology (Gaithersburg, MD) standard ultrasonic power source, capable of producing acoustic fields in the frequency range from approximately 1 to 21 MHz, was circulated to 3 laboratories. RESULTS: The results of the calibrations indicate that the overall uncertainty in acoustic power measurements depends on the target and the measurement method. In the case of radiation force balance measurements with an absorbing target, the largest discrepancy between the available National Institute of Standards and Technology-calibrated results and the reported data was 10.6% at approximately 2.5 MHz. At higher frequencies, beyond 10 MHz, the largest discrepancy reported with an absorbing target was 8.4%. For a reflecting target, the largest discrepancies were 16.2% at approximately 3.7 MHz and 15.4% at about 10 MHz. The largest discrepancy identified for the planar scanning technique below 10 MHz was 7.4% at 3.7 MHz. CONCLUSIONS: The results obtained suggest that an absorbing target may be preferable for acoustic power measurements with radiation force balance. In a group that consists of 2 research laboratories and 1 manufacturer, the power measurements agreed within 16%.

Acoustics↗

PubMed2002

A unified model for the speed of sound in cranial bone based on genetic algorithm optimization.

The density and structure of bone is highly heterogeneous, causing wide variations in the reported speed of sound for ultrasound propagation. Current research on the propagation of high intensity focused ultrasound through an intact human skull for non-invasive therapeutic action on brain tissue requires a detailed model for the acoustic velocity in cranial bone. Such models have been difficult to derive empirically due to the aforementioned heterogeneity of bone itself. We propose a single unified model for the speed of sound in cranial bone based upon the apparent density of bone by CT scan. This model is based upon the coupling of empirical measurement, theoretical acoustic simulation and genetic algorithm optimization. The phase distortion caused by the presence of skull in an acoustic path is empirically measured. The ability of a theoretical acoustic simulation coupled with a particular speed-of-sound model to predict this phase distortion is compared against the empirical data, thus providing the fitness function needed to perform genetic algorithm optimization. By performing genetic algorithm optimization over an initial population of candidate speed-of-sound models, an ultimate single unified model for the speed of sound in both the cortical and trabecular regions of cranial bone is produced. The final model produced by genetic algorithm optimization has a nonlinear dependency of speed of sound upon local bone density. This model is shown by statistical significance to be a suitable model of the speed of sound in bone. Furthermore, using a skull that was not part of the optimization process, this model is also tested against a published homogeneous speed-of-sound model and shown to return an improved prediction of transcranial ultrasound propagation.

Algorithms↗

PubMed2002

Association of rectal toxicity with thermal dose parameters in treatment of locally advanced prostate cancer with radiation and hyperthermia.

PURPOSE: Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer. METHODS AND MATERIALS: Thirty patients with T2b-T3b disease (1992 American Joint Committee On Cancer criteria) enrolled in a Phase II study of external beam radiation +/- androgen-suppressive therapy with two transrectal ultrasound hyperthermia treatments were assessed for rectal toxicity. Prostatic and anterior rectal wall temperatures were monitored for all treatments. Rectal wall temperatures were limited to 40 degrees C in 19 patients, 41 degrees C in 3 patients, and 42 degrees C in 8 patients. Logistic regression was used to estimate the log hazard of developing National Cancer Institute Common Toxicity Criteria Grade 2 toxicity based on temperature parameters. The following were calculated: hazard ratios, 95% confidence intervals, p values for statistical significance of each parameter, and proportion of variability explained for each parameter. RESULTS: Gastrointestinal toxicity was limited to Grade 2. The rate of acute Grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40 degrees C. In this group, 7 of 11 patients experienced acute Grade 2 proctitis, as opposed to 3 of 19 patients in the group with rectal wall temperatures limited to 40 degrees C (p = 0.004). Preliminary assessment of long-term toxicity revealed no differences in toxicity. Hazard ratios for acute Grade 2 proctitis for allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax were 9.33 (p = 0.01), 3.66 (p = 0.03), and 2.29 (p = 0.08), respectively. A model combining these three parameters explained 48.6% of the variability among groups. CONCLUSION: Rectal toxicity correlates with maximum allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax for patients undergoing transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer. Further definition of this association of thermal dose parameters with rectal toxicity in treatment of pelvic malignancies with hyperthermia should advance the goal of delivering thermal therapy in an effective yet safe manner.

Digestive System↗