Main Uncertainties in the RF Ultrasound Scanning Simulation of the Standard Ultrasound Phantoms.

Ultrasound echoscopy technologies are continuously evolving towards new modalities including quantitative parameter imaging, elastography, 3D scanning, and others. The development and analysis of new methods and algorithms require an adequate digital simulation of radiofrequency (RF) signal transformations. The purpose of this paper is the quantitative evaluation of RF signal simulation uncertainties in resolution and contrast reproduction with the model of a phased array transducer. The method is based on three types of standard physical phantoms. Digital 3D models of those phantoms are composed of point scatterers representing the weak backscattering of the background material and stronger backscattering from inclusions. The simulation results of echoscopy with sector scanning transducer by Field II software are compared with the RF output of the Ultrasonix scanner after scanning standard phantoms with 2.5 MHz phased array. The quantitative comparison of axial, lateral, and elevation resolutions have shown uncertainties from 9 to 22% correspondingly. The echoscopy simulation with two densities of scatterers is compared with contrast phantom imaging on the backscattered RF signals and B-scan reconstructed image, showing that the main sources of uncertainties limiting the echoscopy RF signal simulation adequacy are an insufficient knowledge of the scanner and phantom's parameters. The attempt made for the quantitative evaluation of simulation uncertainties shows both problems and the potential of echoscopy simulation in imaging technology developments. The analysis presented could be interesting for researchers developing quantitative ultrasound imaging and elastography technologies looking for simulated raw RF signals comparable to those obtained from real ultrasonic scanning.

Investigation of Radiofrequency Ultrasound-Based Fibrotic Tissue Strain Imaging Method Employing Endogenous Motion.

OBJECTIVES: The paper presents the results of an initial clinical study, which were obtained using the strain elastography imaging method based on radio frequency ultrasound signal analysis. METHODS: The technique employs endogenous motion of the liver induced by beating heart and vascular pulsatility as an excitation source of tissue microdisplacement. The potential for fibrotic tissue characterization was demonstrated using a clinical data set of radio frequency ultrasound signals (23 healthy controls, 21 subjects with hepatitis, and 16 subjects with liver cirrhosis). Parametric maps, which represent the tissue strain, were derived from the gradient of the integrated spectral coefficient parameter, and correlations with the stage of liver disease were evaluated. Average endogenous strain derived from the gradient of the integrated spectral coefficient parameter and variability (standard deviation) of the strain were evaluated in the rectangular regions of interest (sizes, 1 × 1 and 2 × 2 cm) defined by the observer. The assessment of strain was performed in different frequency subbands of endogenous motion (0-10 Hz and 10-20 Hz). RESULTS: The best distinction between the groups was observed for the average strain derived from the gradient of the integrated spectral coefficient parameter: the controls, 13.30 ± 6.62; hepatitis, 7.12 ± 7.45; cirrhosis, 3.95 ± 2.44 µm/cm (region of interest, 1 × 1 cm; frequency subband 0-10 Hz), and 10.48 ± 6.02, 8.27 ± 5.41, 3.89 ± 2.07 µm/cm, respectively (2 × 2 cm, 0-10 Hz). CONCLUSION: The investigated strain parameters showed statistically significant differences (P < .001) for the different stages of liver fibrosis in most of the cases and proved this method to be feasible.

Transcranial Ultrasonographic Image Analysis System for Decision Support in Parkinson Disease.

OBJECTIVES: Transcranial ultrasonography (US) is a relatively new neuroimaging modality proposed for early diagnostics of Parkinson disease (PD). The main limitation of transcranial US image-based diagnostics is a high degree of subjectivity caused by low quality of the transcranial images. The article presents a developed image analysis system and evaluates the potential of automated image analysis on transcranial US. METHODS: The system consists of algorithms for the segmentation and assessment of informative brain regions (midbrain and substantia nigra) and a decision support subsystem, which is equipped with 64 classification algorithms. Transcranial US images of 191 participants (118 patients with a clinical PD diagnosis and 73 healthy control participants) were analyzed. RESULTS: The diagnostic sensitivity and specificity achieved by the proposed system were 85% and 75%, respectively. CONCLUSIONS: Digital transcranial US image analysis is challenging, and the application of a such system as the sole instrument for decisions in clinical practice remains inconclusive. However, the proposed system could be used as a supplementary tool for automated assessment of US parameters for decision support in PD diagnostics and to reduce observer variability.

Analysis of Metrics for Molecular Sonotransfer in Vitro.

Ultrasound induced microbubble (MB) cavitation is used to significantly enhance cell membrane permeabilization, thereby allowing delivery of various therapeutic agents into cells. In order to monitor and quantitatively control the extent of cavitation the uniform dosimetry model is needed. In present study we have simultaneously performed quantitative evaluation of three main sonoporation factors: (1) MB concentration, (2) MB cavitation extent, and (3) doxorubicin (DOX) sonotransfer into Chinese hamster ovary cells. MB concentration measurement results and passively recorded MB cavitation signals were used for MB sonodestruction rate and spectral root-mean-square (RMS) calculations, respectively. Subsequently, time to maximum value of RMS and inertial cavitation dose (ICD) quantifications were performed for every acoustic pressure value. This comprehensive research has led not only to explanation of relation of ICD and MB sonodestruction rate but also to the development of a new sonoporation metric: the inverse of time to maximum value of RMS (1/time to maximum value of RMS). ICD and MB sonodestruction rate intercorrelation and correlation with DOX sonotransfer suggest inertial cavitation to be the key mechanism for cell sonoporation. All these metrics were successfully used for doxorubicin sonotransfer prediction (R(2) > 0.9, p < 0.01) and therefore shows feasibility to be applied for future dosimetric applications for ultrasound-mediated drug and gene delivery.

Microbubble sonodestruction rate as a metric to evaluate sonoporation efficiency.

OBJECTIVES: The efficiency of sonoporation is directly related to microbubble cavitation and can be dependent on the microbubble sonodestruction rate. The objective of this study was to investigate whether the rate of microbubble sonodestruction can be used as a parameter to develop an implicit dosimetric method for sonoporation efficiency evaluation. METHODS: To evaluate the rate of microbubble sonodestruction as a function of the ultrasound (US) peak negative ultrasound pressure, 12-MHz diagnostic US was used in the B-scan mode. Chinese hamster ovary cells were exposed to therapeutic US at 880 kHz in the absence or presence of microbubbles. The sonoporation efficiency was evaluated by the sonotransfer of bleomycin, a cytotoxic, membrane-impermeable anticancer drug. RESULTS: At a low microbubble sonodestruction rate of 1/τ < 0.5 second(-1) (τ providing the time necessary to decrease the microbubble concentration to 37% of its initial value), cell viability remained basically unaffected, but the percentage of sonoporated cells did not reach 10%. At higher microbubble sonodestruction rates, the efficiencies of irreversible and reversible sonoporation started to increase linearly and reached the plateau at 5 seconds(-1). CONCLUSIONS: These results show that the microbubble sonodestruction rate can be used to predict the percentage of reversible and irreversible sonoporation.

Dosimetric assessment of antitumor treatment by enhanced bleomycin delivery via electroporation and sonoporation.

Targeted and controlled techniques of intratumoral delivery of chemotherapeutic agents are under extensive development, since they diminish detrimental side-effects of conventional anticancer drugs. We investigated the effectiveness of chemotherapy using bleomycin (1 mg/ml) and Sonovue microbubbles combined with: electroporation (EP), mainly designed for subcutaneous tumor therapy, and sonoporation (SP) - for deeper localized tumors. Research was performed on hepatoma MH-22A tumors in murine models, exposed to EP or SP and combined (EP + SP) treatment. Animal survival time and the rate/ speed of tumor growth reduction were examined. Study demonstrated that both EP or SP and their combination (EP + SP) were able to induce the reduction of tumor volume from the 3rd day after treatment. The employment of EP before SP allowed to significantly reduce the values of inertial cavitation dose (ICD), necessary to induce complete tumor reduction and prolong animal survival. The analysis of ultrasound (US) side-scattered signals and B-scan imaging indicated the occurrence of inertial cavitation at our experimental conditions. Strong (R2 = 0.88; p < 0.0001) correlation of ICD with the survival time of corresponding unrecovered mice indicates the option for the dosimetric control and standardization of cavitation activities for in vivo practice.

Simulation of Ultrasound RF Signals Backscattered from a 3D Model of Pulsating Artery Surrounded by Tissue.

Arterial stiffness is an independent predictor of cardiovascular events. The motion of arterial tissues during the cardiac cycle is important as a mechanical deformation representing vessel elasticity and is related to arterial stiffness. In addition, arterial pulsation is the main source of endogenous tissue micro-motions currently being studied for tissue elastography. Methods based on artery motion detection are not applied in clinical practice these days, because they must be carefully investigated in silico and in vitro before wide usage in vivo. The purpose of this paper is to propose a dynamic 3D artery model capable of reproducing the biomechanical behavior of human blood vessels surrounded by elastic tissue for endogenous deformation elastography developments and feasibility studies. The framework is based on a 3D model of a pulsating artery surrounded by tissue and simulation of linear scanning by Field II software to generate realistic dynamic RF signals and B-mode ultrasound image sequential data. The model is defined by a spatial distribution of motions, having patient-specific slopes of radial and longitudinal motion components of the artery wall and surrounding tissues. It allows for simulating the quantified mechanical micro-motions in the volume of the model. Acceptable simulation errors calculated between modeled motion patterns and those estimated from simulated RF signals and B-scan images show that this approach is suitable for the development and validation of elastography algorithms based on motion detection.

Diagnostic Ability of Radiofrequency Ultrasound in Parkinson's Disease Compared to Conventional Transcranial Sonography and Magnetic Resonance Imaging.

We aimed to estimate tissue displacements' parameters in midbrain using ultrasound radiofrequency (RF) signals and to compare diagnostic ability of this RF transcranial sonography (TCS)-based dynamic features of disease affected tissues with conventional TCS (cTCS) and magnetic resonance imaging (MRI) while differentiating patients with Parkinson's disease (PD) from healthy controls (HC). US tissue displacement waveform parametrization by RF TCS for endogenous brain tissue motion, standard neurological examination, cTCS and MRI data collection were performed for 20 PD patients and for 20 age- and sex-matched HC in a prospective manner. Three logistic regression models were constructed, and receiver operating characteristic (ROC) curve analyses were applied. The model constructed of RF TCS-based brain tissue displacement parameters-frequency of high-end spectra peak and root mean square-revealed presumably increased anisotropy in the midbrain and demonstrated rather good diagnostic ability in the PD evaluation, although it was not superior to that of the cTCS or MRI. Future studies are needed in order to establish the true place of RF TCS detected tissue displacement parameters for the evaluation of pathologically affected brain tissue.

Ultrasonic Assessment of the Medial Temporal Lobe Tissue Displacements in Alzheimer's Disease.

We aim to estimate brain tissue displacements in the medial temporal lobe (MTL) using backscattered ultrasound radiofrequency (US RF) signals, and to assess the diagnostic ability of brain tissue displacement parameters for the differentiation of patients with Alzheimer's disease (AD) from healthy controls (HC). Standard neuropsychological evaluation and transcranial sonography (TCS) for endogenous brain tissue motion data collection are performed for 20 patients with AD and for 20 age- and sex-matched HC in a prospective manner. Essential modifications of our previous method in US waveform parametrization, raising the confidence of micrometer-range displacement signals in the presence of noise, are done. Four logistic regression models are constructed, and receiver operating characteristic (ROC) curve analyses are applied. All models have cut-offs from 61.0 to 68.5% and separate AD patients from HC with a sensitivity of 89.5% and a specificity of 100%. The area under a ROC curve of predicted probability in all models is excellent (from 95.2 to 95.7%). According to our models, AD patients can be differentiated from HC by a sharper morphology of some individual MTL spatial point displacements (i.e., by spreading the spectrum of displacements to the high-end frequencies with higher variability across spatial points within a region), by lower displacement amplitude differences between adjacent spatial points (i.e., lower strain), and by a higher interaction of these attributes.

Quantification of Endogenous Brain Tissue Displacement Imaging by Radiofrequency Ultrasound.

The purpose of this paper is a quantification of displacement parameters used in the imaging of brain tissue endogenous motion using ultrasonic radiofrequency (RF) signals. In a preclinical study, an ultrasonic diagnostic system with RF output was equipped with dedicated signal processing software and subject head-ultrasonic transducer stabilization. This allowed the use of RF scanning frames for the calculation of micrometer-range displacements, excluding sonographer-induced motions. Analysis of quantitative displacement estimates in dynamical phantom experiments showed that displacements of 55 µm down to 2 µm were quantified as confident according to Pearson correlation between signal fragments (minimum p ≤ 0.001). The same algorithm and scanning hardware were used in experiments and clinical imaging which allows translating phantom results to Alzheimer's disease patients and healthy elderly subjects as examples. The confident quantitative displacement waveforms of six in vivo heart-cycle episodes ranged from 8 µm up to 263 µm (Pearson correlation p ≤ 0.01). Displacement time sequences showed promising possibilities to evaluate the morphology of endogenous displacement signals at each point of the scanning plane, while displacement maps-regional distribution of displacement parameters-were essential for tissue characterization.

Endogenous motion of liver correlates to the severity of portal hypertension.

BACKGROUND: Degree of portal hypertension (PH) is the most important prognostic factor for the decompensation of liver cirrhosis and death, therefore adequate care for patients with liver cirrhosis requires timely detection and evaluation of the presence of clinically significant PH (CSPH) and severe PH (SPH). As the most accurate method for the assessment of PH is an invasive direct measurement of hepatic venous pressure gradient (HVPG), the search for non-invasive methods to diagnose these conditions is actively ongoing. AIM: To evaluate the feasibility of parameters of endogenously induced displacements and strain of liver to assess degree of PH. METHODS: Of 36 patients with liver cirrhosis and measured HVPG were included in the case-control study. Endogenous motion of the liver was characterized by derived parameters of region average tissue displacement signal (d antero, dr etro, d RMS) and results of endogenous tissue strain imaging using specific radiofrequency signal processing algorithm. Average endogenous strain µ and standard deviation σ of strain were assessed in the regions of interest (ROI) (1 cm × 1 cm and 2 cm × 2 cm in size) and different frequency subbands of endogenous motion (0-10 Hz and 10-20 Hz). RESULTS: Four parameters showed statistically significant (P < 0.05) correlation with HVPG measurement. The strongest correlation was obtained for the standard deviation of strain (estimated at 0-10 Hz and 2 cm × 2 cm ROI size). Three parameters showed statistically significant differences between patient groups with CSPH, but only d retro showed significant results in SPH analysis. According to ROC analysis area under the curve (AUC) of the σ ROI[0…10Hz, 2 cm × 2 cm] parameter reached 0.71 (P = 0.036) for the diagnosis of CSPH; with a cut-off value of 1.28 µm/cm providing 73% sensitivity and 70% specificity. AUC for the diagnosis of CSPH for µ ROI[0…10Hz, 1 cm × 1 cm] was 0.78 (P = 0.0024); with a cut-off value of 3.92 µm/cm providing 73% sensitivity and 80% specificity. D retro parameter had an AUC of 0.86 (P = 0.0001) for the diagnosis of CSPH and 0.84 (P = 0.0001) for the diagnosis of SPH. A cut-off value of -132.34 µm yielded 100% sensitivity for both conditions, whereas specificity was 80% and 72% for CSPH and SPH respectively. CONCLUSION: The parameters of endogenously induced displacements and strain of the liver correlated with HVPG and might be used for non-invasive diagnosis of PH.

Carotid Wall Longitudinal Motion in Ultrasound Imaging: An Expert Consensus Review.

Motion extracted from the carotid artery wall provides unique information for vascular health evaluation. Carotid artery longitudinal wall motion corresponds to the multiphasic arterial wall excursion in the direction parallel to blood flow during the cardiac cycle. While this motion phenomenon has been well characterized, there is a general lack of awareness regarding its implications for vascular health assessment or even basic vascular physiology. In the last decade, novel estimation strategies and clinical investigations have greatly advanced our understanding of the bi-axial behavior of the carotid artery, necessitating an up-to-date review to summarize and classify the published literature in collaboration with technical and clinical experts in the field. Within this review, the state-of-the-art methodologies for carotid wall motion estimation are described, and the observed relationships between longitudinal motion-derived indices and vascular health are reported. The vast number of studies describing the longitudinal motion pattern in plaque-free arteries, with its putative application to cardiovascular disease prediction, point to the need for characterizing the added value and applicability of longitudinal motion beyond established biomarkers. To this aim, the main purpose of this review was to provide a strong base of theoretical knowledge, together with a curated set of practical guidelines and recommendations for longitudinal motion estimation in patients, to foster future discoveries in the field, toward the integration of longitudinal motion in basic science as well as clinical practice.

Investigation of Microbubble Cavitation-Induced Calcein Release from Cells In Vitro.

In the present study, microbubble (MB) cavitation signal analysis was performed together with calcein release evaluation in both pressure and exposure duration domains of the acoustic field. A passive cavitation detection system was used to simultaneously measure MB scattering and attenuation signals for subsequent extraction efficiency relative to MB cavitation activity. The results indicate that the decrease in the efficiency of extraction of calcein molecules from Chinese hamster ovary cells, as well as cell viability, is associated with MB cavitation activity and can be accurately predicted using inertial cavitation doses up to 0.18 V × s (R2 > 0.9, p < 0.0001). No decrease in additional calcein release or cell viability was observed after complete MB sonodestruction was achieved. This indicates that the optimal exposure duration within which maximal sono-extraction efficiency is obtained coincides with the time necessary to achieve complete MB destruction. These results illustrate the importance of MB inertial cavitation in the sono-extraction process. To our knowledge, this study is the first to (i) investigate small molecule extraction from cells via sonoporation and (ii) relate the extraction process to the quantitative characteristics of MB cavitation acoustic spectra.

Frequency dependence of speckle in continuous-wave ultrasound with implications for blood perfusion measurements.

Speckle in continuous wave (CW) Doppler has previously been found to cause large variations in detected Doppler power in blood perfusion measurements, where a large number of blood vessels are present in the sample volume. This artifact can be suppressed by using a number of simultaneously transmitted frequencies and averaging the detected signals. To optimize the strategy, statistical properties of speckle in CW ultrasound need to be known. This paper presents analysis of the frequency separation necessary to obtain independent values of the received power for CW ultrasound using a simplified mathematical model for insonation of a static, lossless, statistically homogeneous, weakly scattering medium. Specifically, the autocovariance function for received power is derived, which functionally is the square of the (deterministic) autocorrelation function of the effective sample volumes produced by the transducer pair for varying frequencies, at least if a delta correlated medium is assumed. A marginal broadening of the modeled autocovariance functions is expected for insonation of blood. The theory is applicable to any transducer aperture, but has been experimentally verified here with 5-MHz, 6.35-mm circular transducers using an agar phantom containing small, randomly dispersed glass particles. A similar experimental verification of a transducer used in multiple-frequency blood perfusion measurements shows that the model proposed in this paper is plausible for explaining the decorrelation between different channels in such a measurement.

Investigation of intracranial media ultrasonic monitoring model.

The objectives are to investigate the peculiarities of the ultrasound pulse propagation through human extra/intracranial media by mathematical simulation and to confirm the simulation results experimentally by proving the suitability of the ultrasonic time-of-flight measurement method for human intracranial media (IM) physiological non-invasive monitoring. The mathematical model of ultrasound pulse propagation through the human extra/intracranial media is described. The simulation of various physiological phenomena were performed to determine the relationship between the characteristics of the transmitted ultrasound pulse through the human head and the acoustic properties of the IM. It is shown that non-invasive monitoring of the IM acoustic properties is possible by measuring the changes of the ultrasonic signal time-of-flight and the oscillation period. The influence made by variations in acoustic parameters of the external tissue/skull bones on the non-invasive measurement data is investigated and methods of compensation of that influence are presented. The models were applied for developing of a new non-invasive sonographic intracranial pressure (ICP) monitor (Vittamed). Comparative studies of this monitor with the invasive ICP monitor (Camino) have shown the possibility of achieving clinically acceptable accuracy of the long term non-invasive ICP monitoring of head injured patients in intensive care units.

Modelling of nonlinear effects and the response of ultrasound contrast micro bubbles: simulation and experiment.

The propagation of diagnostic ultrasonic imaging pulses in tissue and their interaction with contrast micro bubbles is a very complex physical process, which we assumed to be separable into three stages: pulse propagation in tissue, the interaction of the pulse with the contrast bubble, and the propagation of the scattered echo. The model driven approach is used to gain better knowledge of the complex processes involved. A simplified way of field simulation is chosen due to the complexity of the task and the necessity to estimate comparative contributions of each component of the process. Simulations are targeted at myocardial perfusion estimation. A modified method for spatial superposition of attenuated waves enables simulations of low intensity pulse pressure fields from weakly focused transducers in a nonlinear, attenuating, and liquid-like biological medium. These assumptions enable the use of quasi-linear calculations of the acoustic field. The simulations of acoustic bubble response are carried out with the Rayleigh-Plesset equation with the addition of radiation damping. Theoretical simulations with synthesised and experimentally sampled pulses show that the interaction of the excitation pulses with the contrast bubbles is the main cause of nonlinear scattering, and a 2-3 dB increase of second harmonic amplitude depends on nonlinear distortions of the incident pulse.

Development of teleconsultations systems for e-health.

Two prototype telemedicine systems have been developed: 1) a wireless system for status assessment of cardiology patients (WSCP), 2) a system for medical image management and teleconsultations (IMTS). The former system enables the patient to record an ECG on a personal digital assistant (PDA), view it and send it via a wireless connection. The doctor on duty is then able to view the received ECG and make appropriate decisions, also to apply for consultation by sending the received ECG to the PDA of a cardiology expert. The system logs all performed operations. The hardware used in the system consists of personal computers (PCs), PDAs, analog-digital converters, ECG sensors and GPRS modems. Software consists of programs for patients, doctors on duty, cardiology experts and administration, along with a central database. The second system is intended to be used by professional doctors for management of collected images and for teleconsultations via videoconferencing in order to obtain a second opinion. The system provides an integrated environment eliminating the need to jump between many applications. By using the system, doctors are able to acquire images from analog and digital cameras, process and enhance them, as well as upload them to local or remote databases. Doctors are also able to design custom database forms. The teleconsultation part of the system supports video and audio over ISDN and TCP-IP, using both a hardware codec (Zydacron Z360) and a software codec (based on MS Netmeeting). Images are sent from one client to another using the standard protocol T.120. Images become synchronized immediately upon reception by another client.

Backscattered ultrasound from contrast microbubbles: effects of tissue and bubble interaction.

The propagation of diagnostic ultrasonic imaging pulses in tissue and their interaction with contrast microbubbles is a complex physical process. Our model driven approach is used to gain better knowledge of the different processes involved in the generation of the backscattered contrast echo. It can be divided into three separable stages: linear and nonlinear wave propagation in tissue, the resulting echo from the pulse interaction with the contrast microbubble, and the propagation of the scattered echo. A simplified approach of field simulation is chosen due to the complexity of the task and necessity to estimate comparative contributions of each component of the process. A modified method for spatial superposition of attenuated waves was further developed to enable simulations of low intensity pulse fields in nonlinear attenuating and liquid-like biological medium using weakly focused transducers. Simulations of the acoustic bubble response are carried out with Rayleigh-Plesset equation with the addition of the radiation damping. Theoretical simulations show that contrast bubbles interaction with excitation pulses is the main cause of nonlinear distortions, and a 2-3 dB increase of second harmonic amplitude depends on nonlinear distortions of incident pulse.