Hiroshi Furuhata

Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro

OBJECTIVE Refinements of treatment methods are sought to rapidly reduce the volume of intracranial clots and to decrease patient exposure to possible complications of thrombolytic therapy for intracranial hematomas. We assessed the possibility of adding ultrasonication using model systems including human blood clots and temporal bone in vitro. METHODS The transmittance of ultrasound through temporal bone obtained at autopsy was compared between the frequencies 211.5 KHz and 1.03 MHz, using a meter to determine the power delivered. The frequency 211.5 KHz was chosen to assess the ultrasound effect on the weight of 24-hour-old clots prepared from human blood after exposures at 37 degrees C to 2 mg/ml urokinase with no additional treatment, ultrasound, or agitation during an interval of up to 12 hours. At these times, fibrin degradation products also were measured. RESULTS The transmittance of low-frequency ultrasound (211.5 KHz) through temporal bone was approximately 40%, which is four times higher than that of high-frequency ultrasound (1.03 MHz). Ultrasound but not agitation significantly increased clot lysis (140% of lysis with urokinase alone), with correspondingly increased fibrin degradation products. CONCLUSION We conclude that low-frequency ultrasound transmits well through human temporal bone and enhances thrombolysis in vitro. Clinically, this method may be promising for reducing dosages of thrombolytic agents and shortening the period of clot removal.

Relationship between the pressure and diameter of the carotid artery in humans.

Abstract The purpose of this study was to examine the assumption of similarity between pressure and diameter-change waveforms in humans. We measured carotid arterial pressure and diameter change, simultaneously, in six patients with heart disease. In all patients, the carotid arterial pressure–diameter relationship could, in practice, be regarded as being linear.

Can Transcranial Ultrasonication Increase Recanalization Flow With Tissue Plasminogen Activator

Background and Purpose— In thrombolytic therapy for acute ischemic stroke, it is essential to obtain rapid thrombolysis before ischemic neuronal injury occurs. To develop a new technique of thrombolysis for acute ischemic stroke, the effect of transcranially applied ultrasound (TUS) on thrombolysis was examined. Methods— An occlusion model of rabbit femoral artery was produced with thrombin after establishment of stenotic flow and endothelial damage. After stable occlusion was confirmed, monteplase (mtPA) was administered intravenously, and ultrasound (490 kHz, 0.13 W/cm2) was applied through a piece of temporal bone (TUS group; n=9). The control group received mtPA alone (tissue plasminogen activator [tPA] group; n=12). To verify the efficacy of TUS, femoral artery flow was measured during the procedure. Results— The recanalization ratio was 16.7% (2 of 12) in the tPA group and 66.7% (6 of 9) in the TUS group. The recanalization ratio in the TUS group was higher than that in the tPA group (P =0.03). Patency flow ratio, which was defined as recanalization flow divided by baseline flow, of the TUS group (44.6±13.9%) was significantly greater than that of the tPA group (9.9±6.8%) at 60 minutes (P =0.025). Patency flow ratio became higher in the TUS group than in the tPA group between 20 and 30 minutes from the start of thrombolysis. Conclusions— Low-frequency and low-intensity TUS enhanced thrombolysis by mtPA in a rabbit femoral artery occlusion model. This technique should be clinically useful for thrombolysis in acute ischemic stroke.

Dual-frequency ultrasound imaging and therapeutic bilaminar array using frequency selective isolation layer

A new ultrasound array transducer with two different optimal frequencies designed for diagnosis and therapy integration in Doppler imaging-based transcranial sonothrombolysis is described. Previous studies have shown that respective frequencies around 0.5 and 2 MHz are suitable for sonothrombolysis and Doppler imaging. Because of the small acoustic window available for transcranial ultrasound exposure, it is highly desirable that both therapeutic and diagnostic ultrasounds pass through the same aperture with high efficiency. To achieve such a dual-frequency array transducer, we propose a bilaminar array, having an array for imaging and another for therapy, with a frequency selective isolation layer between the two arrays. The function of this layer is to isolate the imaging array from the therapy array at 2 MHz without disturbing the 0.5-MHz ultrasound transmission. In this study, we first used a 1-D model including two lead zirconate titanate (PZT) layers separated by an isolation layer for intuitive understanding of the phenomena. After that, we optimized the acoustic impedance and thickness of the isolation layer by analyzing pulse propagation in a 2-D model by conducting a numerical simulation with commercially available software. The optimal acoustic impedance and thickness are 3 to 4 MRayl and ¿/10, respectively. On the basis of the optimization, a prototype array transducer was fabricated, and the spatial resolutions of the Doppler images it obtained were found to be practically the same as those obtained through conventional imaging array transducers.

Bubble Generation by Standing Wave in Water Surrounded by Cranium with Transcranial Ultrasonic Beam

Low-frequency ultrasound, typically less than 1 MHz, is suitable for enhancing thrombolysis because it penetrates the cranium effectively. However, intracerebral hemorrhages after transcranial insonation in clinical trials at 300 Hz have been reported. In this study, acoustic bubble formation in a standing wave with a 617 kHz ultrasonic beam in water surrounded by a contoured piece of a human cranium was detected by ultrasound B-mode imaging. This bubble formation was indirect evidence that standing-wave formation led to cavitational adverse effects in brain tissue at the place of reflection by transcranial insonation at a relatively low ultrasonic frequency. A way of suppressing cavitation after bubble formation was also investigated. The efficiency of nucleation of bubbles was highly dependent on pulse duration at a constant total acoustic power. The obtained result suggests that inertial cavitation can be suppressed while preserving the efficiency of thrombolysis by temporally changing the acoustic condition before resonant bubble formation.

Effective and safe conditions of low-frequency transcranial ultrasonic thrombolysis for acute ischemic stroke: neurologic and histologic evaluation in a rat middle cerebral artery stroke model.

Background and Purpose— Transcranial ultrasound (TUS) enhances thrombolysis and is expected to be useful for the treatment of ischemic stroke. However, neither its effectiveness in improving neurologic outcome nor its safety in living tissue has been fully established. We examined the efficacy and safety of low-frequency TUS under appropriate conditions of ultrasound for thrombolytic treatment in a rat middle cerebral artery stroke model. Methods— Sixty-five male Wistar rats were used. Rats with right middle cerebral artery stroke exhibiting left hemiparesis were blindly selected and randomly assigned to 1 of 3 groups: (1) control, no therapy; (2) tPA, intravenous administration of tissue plasminogen activator 3 hours after middle cerebral artery stroke, or (3) TUS, tPA administration and application of TUS (490 kHz, continuous wave, at an intensity of 0.8 W/cm2). Twenty-four hours after the onset of stroke, neurologic improvement was evaluated and brains were then removed. Thrombolysis at the origin of the right middle cerebral artery was examined. Thrombolysis ratio, cerebral infarct ratio, and rate of histologic evidence of hemorrhage were compared in the 3 groups. Results— Significantly better neurologic improvement (P=0.008), a higher thrombolysis ratio (P=0.041), and a reduction of cerebral infarct volume (P=0.047) were obtained in the TUS group compared with the tPA group, without an increase in hemorrhagic transformation. Conclusions— Our findings suggest that thrombolytic treatment with low-frequency TUS under appropriate conditions could be an effective and safe method of treatment for ischemic stroke.

A facile preparation method of a PFC-containing nano-sized emulsion for theranostics of solid tumors

Theranostics means a therapy conducted in a diagnosis-guided manner. For theranostics of solid tumors by means of ultrasound, we designed a nano-sized emulsion containing perfluoropentane (PFC5). This emulsion can be delivered into tumor tissues through the tumor vasculatures owing to its nano-size, and the emulsion is transformed into a micron-sized bubble upon sonication through phase transition of PFC5. The micron-sized bubbles can more efficiently absorb ultrasonic energy for better diagnostic images and can exhibit more efficient ultrasound-driven therapeutic effects than nano-sized bubbles. For more efficient tumor delivery, smaller size is preferable, yet the preparation of a smaller emulsion is technically more difficult. In this paper, we used a bath-type sonicator to successfully obtain small PFC5-containing emulsions in a diameter of ca. 200nm. Additionally, we prepared these small emulsions at 40°C, which is above the boiling temperature of PFC5. Accordingly, we succeeded in obtaining very small nano-emulsions for theranostics through a very facile method.

COMPARATIVE STUDY OF STANDING WAVE REDUCTION METHODS USING RANDOM MODULATION FOR TRANSCRANIAL ULTRASONICATION

Various transcranial sonotherapeutic technologies have risks related to standing waves in the skull. In this study, we present a comparative study on standing waves using four different activation methods: sinusoidal (SIN), frequency modulation by noise (FMN), periodic selection of random frequency (PSRF), and random switching of both inverse carriers (RSBIC). The standing wave was produced and monitored by the schlieren method using a flat plane and a human skull. The minimum ratio RSW, which is defined by the ratio of the mean of the difference between local maximal value and local minimal value of amplitude to the average value of the amplitude, was 36% for SIN, 24% for FMN, 13% for PSRF, and 4%for RSBIC for the flat reflective plate, and it was 25% for SIN, 11% for FMN, 13% for PSRF, and 5% for RSBIC for the inner surface of the human skull. This study is expected to have a role in the development of safer therapeutic equipment.

Schlieren observation of therapeutic field in water surrounded by cranium radiated from 500 kHz ultrasonic sector transducer

Standing-wave formation in water surrounded by a section of a human cranium, produced by a transcranial 500 kHz ultrasonic beam was observed optically. The ultrasonic beam was generated from a prototype sector-scan phased-array transducer, designed for transcranial enhancement of thrombolysis with tissue plasminogen activator (tPA). The amplitude distribution and the wavefronts of the ultrasonic field were observed in schlieren images. The stripe patterns of the standing waves were clearly seen near the sites of reflection in these images under certain acoustic conditions. No standing wave patterns were detected in basically the same arrangement with a sector-scan phased-array transducer operating at 2 MHz. These findings suggest that standing waves may be formed in the tissue at the positions of reflection by transcranial insonation of a human brain at a relatively low ultrasonic frequency, typically less than 1 MHz. This suggests further the possibility of inducing adverse cavitational effects in brain tissue.

Comparison of Transcranial Brain Tissue Perfusion Images Between Ultraharmonic, Second Harmonic, and Power Harmonic Imaging

Background and Purpose— To clarify optimal brain tissue perfusion images visualized by transcranial ultrasound harmonic imaging, we compared gray-scale integrated backscatter (IBS) images of new ultraharmonic imaging (UHI) and conventional second harmonic imaging (SHI) with power harmonic imaging (PHI) (harmonic B-mode with harmonic power Doppler images) in 10 patients with and 4 without a temporal skull. Methods— Using a SONOS 5500 (Philips), we evaluated transient response images taken after a bolus Levovist injection at a horizontal diencephalic plane via temporal windows. Based on transmitting/receiving frequencies (MHz), 4 imaging procedures using an S3 transducer (SHI2.6 [1.3/2.6], UHI [1.3/3.6], PHI2.6 [1.3/2.6], and PHI3.2 [1.6/3.2]) and 2 imaging procedures using an S4 transducer (SHI3.6 [1.8/3.6] and PHI3.6 [1.8/3.6]) were compared in terms of size and location, peak intensity (PI), contrast area demarcation, and background image quality. Results— In intact skull cases, gray-scale imaging tended to show larger contrast areas than PHI. A large contrast area was most frequently observed in SHI2.6 images, despite there being more high-PI cases in UHI. No contrast area with unclear background was observed in a few cases. In craniectomized cases, all contrast images tended to have large and high PI compared with the intact skull cases. PHI, particularly PHI3.6, demonstrated sharper demarcation and a clearer background than gray-scale imaging. Conclusions— Transcranial gray-scale SHI using a low receiving frequency of 2.6 MHz is the superior method. PHI identifies contrast area localization better than gray-scale imaging and is particularly suitable for intraoperative and postoperative cases.