Biomedical subjects

Kullervo Hynynen

Publications and source records attributed to Kullervo Hynynen.

At least 37 records · Page 2Linked to original sources

PubMed2005

Scanning path optimization for ultrasound surgery.

One of the problems in ultrasound surgery is the long treatment times when large tumour volumes are sonicated. Large tumours are usually treated by scanning the tumour volume using a sequence of individual focus points. During the scanning, it is possible that surrounding healthy tissue suffers from undesired temperature rise. The selection of the scanning path so that the tumour volume is treated as fast as possible while temperature rise in healthy tissue is minimized would increase the efficiency of ultrasound surgery. The main purpose of this paper is to develop a computationally efficient method which optimizes the scanning path. The optimization algorithm is based on the minimum time formulation of the optimal control theory. The developed algorithm uses quadratic cost criteria to obtain the desired thermal dose in the tumour region. The derived method is evaluated with numerical simulations in 3D which are applied to ultrasound surgery of the breast in simplified geometry. Results from the simulations show that the treatment time as well as the total applied energy can be decreased from 16% to 43% as compared to standard sonication. The robustness of the optimized scanning path is studied by varying the perfusion and absorption in the tumour region.

Body Temperature↗

PubMed2005

Intracellular delivery of Bak BH3 peptide by microbubble-enhanced ultrasound.

PURPOSE: To investigate the possibility of intracellular delivery of Bak BH3 peptide using sonoporation effect by microbubble-enhanced ultrasound. METHODS: HeLa and BJAB cells were exposed to 1.696-Mhz focused ultrasound with 2% microbubble contrast agents (OPTISON). Cell-impermeable calcein was used as an indicator for successful sonoporation, and propidium iodide staining was used for cell viability assessment. Peptides were also exposed to ultrasound with OPTISON and analyzed with mass spectrometry for evaluation of stability under ultrasound exposure. The effect of transduced Bak BH3 peptide was evaluated by the cell viability of successfully sonoporated cells. RESULTS: Bak BH3 peptides did not undergo mechanical degradation with microbubble-enhanced ultrasound exposure. With the increase of acoustic energy exposure, the sonoporation efficiency saturated both in BJAB and HeLa cells, while direct cell death rate by ultrasound exposure tended to increase. When BJAB cells were treated with 100 microM Bak BH3 peptides, and ultrasound exposure with ultrasound contrast agents (OPTISON), an increased 35% cell death was confirmed. On the other hand, although HeLa cells had a similar trend, they failed to exhibit statistical significance. CONCLUSIONS: Our results suggest that microbubble-enhanced focused ultrasound peptide transduction is possible. Further optimization of ultrasound exposure conditions may be necessary.

Antineoplastic Agents↗

PubMed2005

A numerical study of transcranial focused ultrasound beam propagation at low frequency.

The feasibility of transcranial ultrasound focusing with a non-moving phased array and without skull-specific aberration correction was investigated using computer simulations. Three cadaver skull CT image data sets were incorporated into an acoustic wave transmission model to simulate transskull ultrasound wave propagation. Using a 0.25 MHz hemispherical array (125 mm radius of curvature, 250 mm diameter, 24 255 elements), the simulated beams could be focused and steered with transducer element driving phases and amplitude adjusted for focal beam steering in water (water-path). A total of 82 foci, spanning wide ranges of distance in the three orthogonal dimensions, were simulated to test the focal beam steering capability inside the three skulls. The acoustic pressure distribution in a volume of 20 x 20 x 20 mm(3) centred at each focus was calculated with a 0.5 mm spacing in each axis. Clearly defined foci were retained through the skulls (skull-path) in most cases. The skull-path foci were on average 1.6 +/- 0.8 mm shifted from their intended locations. The -3 dB skull-path beam width and length were on average 4.3 +/- 1.0 mm and 7.7 +/- 1.8 mm, respectively. The skull-path sidelobe levels ranged from 25% to 55% of the peak pressure values. The skull-path peak pressure levels were about 10%-40% of their water-path counterparts. Focusing low-frequency beam through skull without skull-specific aberration correction is possible. This method may be useful for applying ultrasound to disrupt the blood-brain barrier for targeted delivery of therapeutic or diagnostic agents, or to induce microbubbles, or for other uses of ultrasound in brain where the required power levels are low and the sharp focusing is not needed.

Body Burden↗

PubMed2005

Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications.

The purpose of this study was to test the hypothesis that burst ultrasound in the presence of an ultrasound contrast agent can disrupt the blood-brain barrier (BBB) with acoustic parameters suitable for completely noninvasive exposure through the skull. The 10-ms exposures were targeted in the brains of 22 rabbits with a frequency of 690 kHz, a repetition frequency of 1 Hz, and peak rarefactional pressure amplitudes up to 3.1 MPa. The total exposure (sonication) time was 20 s. Prior to each sonication, a bolus of ultrasound contrast agent was injected intravenously. Contrast-enhanced MR images were obtained after the sonications to detect localized BBB disruption via local enhancement in the brain. Brain sections were stained with H&E, TUNEL, and vanadium acid fuchsin (VAF)-toluidine blue staining. In addition, horseradish peroxidase (HRP) was injected into four rabbits prior to sonications and transmission electron microscopy was performed. The MRI contrast enhancement demonstrated BBB disruption at pressure amplitudes starting at 0.4 MPa with approximately 50%; at 0.8 MPa, 90%; and at 1.4 MPa, 100% of the sonicated locations showed enhancement. The histology findings following 4 h survival indicated that brain tissue necrosis was induced in approximately 70-80% of the sonicated locations at a pressure amplitude level of 2.3 MPa or higher. At lower pressure amplitudes, however, small areas of erythrocyte extravasation were seen. The electron microscopy findings demonstrated HRP passage through vessel walls via both transendothelial and paraendothelial routes. These results demonstrate that completely noninvasive focal disruption of the BBB is possible.

Animals↗

PubMed2005

MR imaging-controlled focused ultrasound ablation: a noninvasive image-guided surgery.

The history of MR-guided FUS demonstrates the need for merging advanced therapy technology with advanced imaging. Without the ability of MR imaging to localize the tumor margins and without the temperature-sensitive imaging that provides the closed-loop control of energy deposition, this method is inadequate for most clinical applications. Given these limitations,high-intensity focused ultrasound initially appeared to have a narrow application area and was not able to compete with other surgical or ablation methods. Today, MR imaging-guided FUS has become a safe and effective means of performing probe-delivered thermal ablations and minimally invasive surgery. Moreover, it has the potential to replace treatments that use ionizing radiation such as radiosurgery and brachytherapy. Although the cost of integrating"big ticket" MR imaging systems with complex and expensive phased arrays is high, this expenditure will largely be offset by eliminating hospitalization and anesthesia and by reducing complications. In effect, an investment in this emerging technology will ultimately redound to the benefit of the health care delivery system and, most important, to the patient. The FUS system provides a safe, repeatable treatment approach for benign tumors (eg, uterine fibroid and breast fibroadenoma) that do not require an aggressive approach. MR-guided FUS can also be used for debulking cancerous tissue. It has already been tested as a breast cancer treatment; its application for other malignancies in the brain, liver, and prostate is under development. MR-guided FUS offers an attractive alternative to conventional surgery because it incorporates intraoperative MR imaging, which provides far more precise target definition than is possible with the surgeon's direct visualization of the lesion. MR-guided FUS is undeniably the most promising interventional MR imaging method in the field of image-guided therapy today. It is applicable not only in the thermal coagulative treatment of tumors but also in several other medical situations for which invasive surgery or radiation may not be treatment options. The use of FUS for treating vascular malformation or functional disorders of the brain is also exciting. It is uniquely applicable for image-guided therapy using targeted drug delivery methods and gene therapy. Further advances in this technology will no doubt improve energy deposition and reduce treatment times. In the near future, FUS will offer a viable alternative to conventional surgery and radiation therapy; in the longer-term, it may also enable a host of targeted treatment methods aimed at eradicating or arresting heretofore intractable diseases such as certain brain malignancies and forms of epilepsy.

Humans↗

PubMed2005

A new ultrasound method for determining the acoustic phase shifts caused by the skull bone.

A potential noninvasive means for obtaining the value of ultrasound (US) phase shifts caused by the skull is examined. Knowledge of these shifts could be used in new methods that restore the focus from an US array after transcranial propagation. In the present study, a pulsed signal was emitted from a single element of a therapeutic US transducer. The reflected signal was then recorded. The data were examined over the band width of the transducer, producing amplitude data as a function of frequency. A periodic appearance of local maxima and minima was observed in the data as a function of frequency. We hypothesize that the amplitude is primarily determined by the superposition of the reflections between the interfaces at the inner and outer surfaces of the skull and between the interior interfaces of trabecular and cortical bone. A homogeneous-layer model was used to predict the forward-propagated phase using the reflection data. Good correlation was found between the numeric calculation and phases measured after propagation through single-layer plastic plates. The method was used on curved three-layer plastic phantoms and four excised human skulls. The procedure could eventually be applied toward phasing multielement arrays. Such an application could have implications in both therapeutic and diagnostic brain procedures.

Humans↗

PubMed2005

MRI-guided ultrasonic heating allows spatial control of exogenous luciferase in canine prostate.

The need for efficient and controlled delivery is one of the major obstacles to clinical use of gene therapy. In this study, we investigated the use of magnetic resonance imaging-monitored ultrasound (US) to induce expression of luciferase after local injection of the construct Ad-HSP-Luc, an adenoviral vector containing a transgene encoding firefly luciferase under the control of the human hsp70B promoter. The hsp promoter allows induction of the associated transgene only in areas that are subsequently heated after infection. US imaging was used to guide the injection of purified virus into both lobes of the prostates of three beagles. At 48 h after injection, the left lobe of the prostate was heated using a 1.5-MHz US transducer driven by a multichannel radiofrequency system and employing an magnetic resonance imaging guidance system. High levels of luciferase expression were observed only in areas exposed to ultrasonic heating. This study demonstrates the feasibility of using ultrasonic heating to control transgene expression spatially using a minimally-invasive approach.

Adenoviridae↗

PubMed2005

MRI-guided targeted blood-brain barrier disruption with focused ultrasound: histological findings in rabbits.

Focused ultrasound offers a method to disrupt the blood-brain barrier (BBB) noninvasively and reversibly at targeted locations. The purpose of this study was to test the safety of this method by searching for ischemia and apoptosis in areas with BBB disruption induced by pulsed ultrasound in the presence of preformed gas bubbles and by looking for delayed effects up to one month after sonication. Pulsed ultrasound exposures (sonications) were performed in the brains of 24 rabbits under monitoring by magnetic resonance imaging (MRI) (ultrasound: frequency = 1.63 MHz, burst length = 100 ms, PRF = 1 Hz, duration = 20 s, pressure amplitude 0.7 to 1.0 MPa). Before sonication, an ultrasound contrast agent (Optison, GE Healthcare, Milwaukee, WI, USA) was injected IV. BBB disruption was confirmed with contrast-enhanced MR images. Whole brain histologic examination was performed using haematoxylin and eosin staining for general histology, vanadium acid fuchsin-toluidine blue staining for ischemic neurons and TUNEL staining for apoptosis. The main effects observed were tiny regions of extravasated red blood cells scattered around the sonicated locations, indicating affected capillaries. Despite these vasculature effects, only a few cells in some of the sonicated areas showed evidence for apoptosis or ischemia. No ischemic or apoptotic regions were detected that would indicate a compromised blood supply was induced by the sonications. No delayed effects were observed either by MRI or histology up to 4 wk after sonication. Ultrasound-induced BBB disruption is possible without inducing substantial vascular damage that would result in ischemic or apoptotic death to neurons. These findings indicate that this method is safe for targeted drug delivery, at least when compared with the currently available invasive methods.

Albumins↗

PubMed2005

Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile.

PURPOSE: Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented. METHODS AND MATERIALS: Thirty-seven patients enrolled on a phase II study of external beam radiation +/- androgen suppression with two transrectal ultrasound hyperthermia treatments were assessed for short- and long-term toxicity. Prostatic and anterior rectal wall temperatures were monitored. Rectal wall temperatures were limited to 40 degrees C (19 patients), 41 degrees C (three patients) and 42 degrees C (15 patients). Univariate logistic regression was used to estimate the log hazard of developing NCI CTC Grade 2 toxicity based on temperature parameters. Hazard ratios, 95% confidence intervals, p-values for statistical significance of each parameter and proportion of variability explained for each of the parameters were calculated. RESULTS: Median follow-up was 42 months. Both short- and long-term GI toxicity were limited to grade 2 or less. Acute grade 2 proctitis was greater for patients with allowable rectal wall temperature of >40 degrees C. Eleven of 18 patients in this group had acute grade 2 proctitis vs three of 19 patients with rectal wall temperatures limited to 40 degrees C (p = 0.004). Long-term grade 2 GI and GU toxicity occurred in 5% and 19% of patients. No late grade 3 or greater toxicity occurred. Late GI and GU toxicity were not associated with the allowable rectal wall temperature. CONCLUSION: Transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer is safe and well tolerated.

Aged↗

PubMed2005

A full-wave Helmholtz model for continuous-wave ultrasound transmission.

A full-wave Helmholtz model of continuous-wave (CW) ultrasound fields may offer several attractive features over widely used partial-wave approximations. For example, many full-wave techniques can be easily adjusted for complex geometries, and multiple reflections of sound are automatically taken into account in the model. To date, however, the full-wave modeling of CW fields in general 3D geometries has been avoided due to the large computational cost associated with the numerical approximation of the Helmholtz equation. Recent developments in computing capacity together with improvements in finite element type modeling techniques are making possible wave simulations in 3D geometries which reach over tens of wavelengths. The aim of this study is to investigate the feasibility of a full-wave solution of the 3D Helmholtz equation for modeling of continuous-wave ultrasound fields in an inhomogeneous medium. The numerical approximation of the Helmholtz equation is computed using the ultraweak variational formulation (UWVF) method. In addition, an inverse problem technique is utilized to reconstruct the velocity distribution on the transducer which is used to model the sound source in the UWVF scheme. The modeling method is verified by comparing simulated and measured fields in the case of transmission of 531 kHz CW fields through layered plastic plates. The comparison shows a reasonable agreement between simulations and measurements at low angles of incidence but, due to mode conversion, the Helmholtz model becomes insufficient for simulating ultrasound fields in plates at large angles of incidence.

Algorithms↗

PubMed2005

Acoustic transmission losses and field alterations due to human scalp hair.

Hair is a potential transmission barrier for diagnostic and therapeutic ultrasound. We tested hair phantoms for insertion losses and field effects at 0.27-2.8 MHz. The negligible losses observed below 0.5 MHz suggest that, at such frequencies, hair removal is unnecessary for low-power imaging or therapeutic applications.

Acoustics↗

PubMed2005

Transcranial ultrasound focus reconstruction with phase and amplitude correction.

Therapeutic and diagnostic ultrasound procedures performed noninvasively through the skull require a reliable method for maintaining acoustic focus integrity after transmission through layered bone structures. This study used a multiple-element, phased-array transducer to reconstruct ultrasound foci through the human skull by amplitude and phase correction. It was previously demonstrated that adaptive phase correction using a multiple-element, focused transducer array yields a significant correction to an acoustic field that has been distorted by the heterogeneities of the skull bone. The introduction of amplitude correction, in a regime in which acoustic pressures from individual transducer array elements are adjusted to be normalized at the focus, has demonstrated a 6% (-0.27 dB) average decrease in acoustic sidelobe acoustic intensity relative to the focal intensity and a 2% (-0.09 dB) average decrease in the full-width-at-half-maximum (FWHM) of the acoustic intensity profile at the focus. These improvements come at the expense of significant ultrasound intensity loss--as much as 30% lower (-1.55 dB)--at the focus because the amplitude correction method requires that, at constant power, a larger proportion of energy is absorbed or reflected by regions of the skull that transmit less energy. In contrast, a second correction method that distributes pressure amplitudes such that the sections of the skull which transmit more ultrasound energy are exposed with higher ultrasound intensities has demonstrated an average sidelobe intensity decrease of 3% (-0.13 dB) with no change in the FWHM at the focus. On average, there was a 2% (0.09 dB) increase in the acoustic intensity at the focus for this inverse amplitude correction method. These results indicate that amplitude correction according to the transmission properties of various segments of the skull have a clear effect on ultrasound energy throughput into a target site within the brain parenchyma.

Algorithms↗

PubMed2005

Focal beam distortion and treatment planning in abdominal focused ultrasound surgery.

Recent clinical trials show promising results in using MRI and MRI-based thermometry to guide focused ultrasound surgery to treat uterine fibroids. During treatment, large variation in the focal temperature distribution has been observed. It is possible that some of this variation is due to abdominal tissue inhomogeneity, which might be causing focal beam distortion, and might largely decrease the focusing ability in deep-seated tissues. The purpose of this study was to numerically demonstrate this effect and also show the feasibility of restoring the focal beam patterns by employing the phase correction procedure for phased arrays. Abdominal MR data from four uterine fibroid patients were obtained to reconstruct the three-dimensional meshes of interfaces used in simulations, and one patient was selected to perform the analysis of key parameters in focused ultrasound surgery. Results show that, without phase correction, the focused beam can be severely distorted while using a frequency above 1 MHz or delivering ring-shape focal patterns. Different focal positions at the same depth may require a different power to induce the same ultrasonic intensity level (up to 179% among the different focal patterns). After adding a phase correction procedure, the distorted focal beams can be restored, and the peak intensity can be largely recovered (up to 85% among the different focal patterns). This study may offer important implications and information for treatment planning toward optimizing focused ultrasound surgery in uterine fibroid or other abdominal tumor treatments.

Abdomen↗

PubMed2005

A magnetic resonance imaging-compatible, large-scale array for trans-skull ultrasound surgery and therapy.

OBJECTIVE: Advances in ultrasound transducer array and amplifier technologies have prompted many intriguing scientific proposals for ultrasound therapy. These include both mildly invasive and noninvasive techniques to be used in ultrasound brain surgery through the skull. In previous work, it was shown how a 500-element hemisphere-shaped transducer could correct the wave distortion caused by the skull with a transducer that operates at a frequency near 0.8 MHz. Because the objective for trans-skull focusing is its ultimate use in a clinical context, a new hemispheric phased-array system has now been developed with acoustic parameters that are optimized to match the values determined in preliminary studies. METHODS: The transducer was tested by focusing ultrasound through ex vivo human skulls and into a brain phantom by means of a phase-adaptive focusing technique. Simultaneously, the procedure was monitored by the use of magnetic resonance guidance and thermometry. RESULTS: The ultrasound focus of a 500-element 30-cm-diameter, 0.81-MHz array could be steered electronically through the skull over a volume of approximately 30 x 30 x 26 mm. Furthermore, temperature monitoring of the inner and outer surfaces of the skull showed that the array could coagulate targeted brain tissue without causing excessive skull heating. CONCLUSIONS: The successful outcome of these experiments indicates that intensities high enough to destroy brain tissue can be produced without excessive heating of the surrounding areas and without producing large magnetic resonance noise and artifacts.

Artifacts↗

PubMed2004

Apoptosis signals in lymphoblasts induced by focused ultrasound.

We investigated the effects of focused ultrasound (FUS) on specific molecular signaling and cellular response in three closely related human Tk6 lymphoblast cell lines that differed only in their p53 status. The applied ultrasound parameters fell between the physical dose range, which is safely used in medical diagnostics (peak pressure<0.1 MPa) and that used for high-energy FUS thermal ablation therapy (peak pressure>10 MPa). Based on cDNA microarrays and protein analysis, we found that FUS at the intermediate peak pressure of 1.5 MPa induced a complex signaling cascade with upregulation of proapoptotic genes [e.g., p53, p21, Thy1 (CD 90)]. Simultaneously, FUS downregulated cellular survival components (e.g., bcl-2, SOD). The p53 status was important for the reaction of the cells to ultrasound. Apoptosis and G1 arrest were induced primarily in p53+ cells, while p53- cells showed less apoptosis but exhibited G2 arrest. Likewise, the proliferation of lymphoblasts was much more strongly inhibited in p53+ than in p53- cells. Microarray analysis further demonstrated an upregulation of genes involved in oxidative stress (e.g., ferritin), suggesting that indirect sonochemical effects via reactive oxygen species play a causative role in the interaction of ultrasound with lymphoblasts. An important characteristic of FUS in therapeutic ultrasound applications is its ability to be administered to the human body in a targeted manner while sparing intermediate tissues. Therefore, our data indicate that this noninvasive, mechanical wave transmission, which is free of ionizing radiation, has the potential to specifically induce localized cell signals and apoptosis.

Apoptosis↗

PubMed2004

Heat-activated liposomal MR contrast agent: initial in vivo results in rabbit liver and kidney.

PURPOSE: To evaluate by using in vivo magnetic resonance (MR) imaging the functionality of a liposomal paramagnetic contrast agent with T1 relaxivity that rapidly and markedly increases at temperatures above the gel-to-liquid crystalline phase transition temperature (T(c)) of the liposome membrane. MATERIALS AND METHODS: Liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) was injected intravenously at a dose of 0.4 or 1.2 mL (containing 10 or 30 micromol of gadolinium, respectively) per kilogram of body weight shortly before the application of focused ultrasound in liver (seven rabbits) or kidney (three rabbits). VX2 tumors had been implanted in liver in four of the rabbits. Eighteen locations in liver (13 in normal tissue, five in tumor) and 12 locations in kidney were sonicated. MR thermometry was performed during sonications. Signal intensity enhancement was evaluated on T1-weighted images acquired after the tissue cooled, and enhanced zones were compared with isotherms at T(c) of the liposome membrane (approximately 57 degrees C) by using Bland-Altman analysis. In liver, enhanced zones also were compared with areas of histologically verified thermal damage. The threshold temperature of enhancement at T1-weighted imaging was verified by monitoring the signal intensity increase after 10 sonications at varied powers in two locations in normal liver tissue. RESULTS: Persistent enhancement was observed on T1-weighted images at all sonicated liver locations. In liver, enhanced zones on T1-weighted images were contiguous both with 57 degrees C isotherms (25 measurements; mean difference +/- SD, 0.4 mm +/- 1.2) and with histologically verified areas of necrosis (seven measurements; mean difference +/- SD, 0.1 mm +/- 0.9). The threshold temperature of enhancement at T1-weighted imaging in normal liver was 53 degrees -57 degrees C. In kidney, enhanced zones on T1-weighted images did not match the isotherms. CONCLUSION: The liposomal contrast agent was effective at in vivo MR thermometry in liver but not in kidney.

Animals↗

PubMed2004

MRI monitoring of heating produced by ultrasound absorption in the skull: in vivo study in pigs.

The purpose of this study was to test the utility of MR thermometry for monitoring the temperature rise on the brain surface and in the scalp induced by skull heating during ultrasound exposures. Eleven locations in three pigs were targeted with unfocused ultrasound exposures (frequency = 690 kHz; acoustic power = 8.2-16.5 W; duration = 20 s). MR thermometry (a chemical shift technique) showed an average temperature rise in vivo of 2.8 degrees C +/- 0.6 degrees C and 4.4 degrees C +/- 1.4 degrees C on the brain surface and scalp, respectively, at an acoustic power level of 10 W. The temperature rise on the scalp agreed with that measured with a thermocouple probe inserted adjacent to the skull (average temperature rise = 4.6 degrees C +/- 1.0 degrees C). Characterization of the transducer showed that the average acoustic intensity was 1.3 W/cm(2) at an acoustic power of 10 W. The ability to monitor the temperature rise next to the skull with MRI-based thermometry, as shown here, will allow for safety monitoring during clinical trials of transcranial focused ultrasound.

Animals↗

PubMed2004

MRI investigation of the threshold for thermally induced blood-brain barrier disruption and brain tissue damage in the rabbit brain.

The ability of MRI-derived thermometry to predict thermally induced tissue changes in the brain was tested, and the thermal thresholds for blood-brain barrier (BBB) disruption and brain tissue damage were estimated. In addition, the ability of standard MRI to detect threshold-level effects was confirmed. These safety thresholds are being investigated to provide guidelines for clinical thermal ablation studies in the brain. MRI-monitored focused ultrasound heating was delivered to 63 locations in 26 rabbits. Tissue changes were detected in T(2)-weighted imaging and T(1)-weighted imaging (with and without contrast) and with light microscopy. The probability for tissue damage as a function of the accumulated thermal dose, the peak temperature achieved, the applied acoustic energy, and the peak acoustic power was estimated with probit regression. The discriminative abilities of these parameters were compared using the areas under the receiver operator characteristic (ROC) curves. In MRI, BBB disruption was observed in contrast-enhanced T(1)-weighted imaging shortly after the ultrasound exposures, sometimes accompanied by changes in T(2)-weighted imaging. Two days later, changes in T(2)-weighted imaging were observed, sometimes accompanied by changes in T(1)-weighted imaging. In histology, tissue damage was seen at every location where MRI changes were observed, ranging from small (diameter <1.0 mm) areas of tissue necrosis to severe vascular damage and associated hemorrhagic infarct. In one location, small (diameter: 0.8 mm) damage was not detected in MRI. The thermal dose and peak temperature thresholds were between 12.3-40.1 equivalent min at 43 degrees C and 48.0-50.8 degrees C, respectively, and values of 17.5 equivalent min at 43 degrees C and 48.4 degrees C were estimated to result in tissue damage with 50% probability. Thermal dose and peak temperature were significantly better predictors than the applied acoustic energy and peak acoustic power (P < 0.01). BBB disruption was always accompanied by tissue damage. The temperature information was better than the applied acoustic power or energy for predicting the damage than the ultrasound parameters. MRI was sensitive in detecting threshold-level damage.

Animals↗