Natural aging and Alzheimer's disease pathology increase susceptibility to focused ultrasound-induced blood-brain barrier opening.

Focused Ultrasound (FUS) paired with systemically-injected microbubbles (µB) is capable of transiently opening the blood-brain barrier (BBBO) for noninvasive and targeted drug delivery to the brain. FUS-BBBO is also capable of modulating the neuroimmune system, further qualifying its therapeutic potential for neurodegenerative diseases like Alzheimer's disease (AD). Natural aging and AD impose significant strain on the brain and particularly the BBB, modifying its structure and subsequently, its functionality. The emerging focus on treating neurodegenerative diseases with FUS-BBBO necessitates an investigation into the extent that age and AD affect the BBB's response to FUS. FUS-BBBO was performed with a 1.5-MHz, geometrically focused transducer operated at 450 kPa and paired with a bolus microbubble injection of 8 × 108 µB/mL. Here we quantify the BBBO, BBB closing (BBBC) timeline, and BBB permeability (BBBP) following FUS-BBBO in male mice with and without AD pathology, aged 10 weeks, one year, or two years. The data presented herein indicates that natural aging and AD pathology may increase initial BBBO volume by up to 34.4% and 40.7% respectively, extend BBBC timeline by up to 1.3 and 1.5 days respectively, and increase BBBP as measured by average Ktrans values up to 80% and 86.1% respectively in male mice. This characterization of the BBB response to FUS-BBBO with age and AD further clarifies the nature and extent of the functional impact of these factors and may offer new considerations for planning FUS-BBBO interventions in aged and AD populations.

Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure.

Focused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. Focused ultrasound combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates, and previous work has demonstrated transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI. However, it is unknown whether opening the BBB affects functional connectivity differently than FUS alone. Thus we applied FUS alone (neuromodulation) and FUS with microbubbles (BBB opening) in the dorsal striatum of lightly anesthetized non-human primates, and compared changes in functional connectivity in major brain networks. We found different alteration patterns between FUS neuromodulation and FUS-mediated BBB opening in several cortical areas, and we also found that applying FUS to a deep brain structure can alter functional connectivity in the default mode network and frontotemporal network.

Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates.

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2-0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons.

The BRICHOS domain is found in human precursor proteins associated with cancer, dementia (Bri2) and amyloid lung disease (proSP-C). Recombinant human (rh) proSP-C and Bri2 BRICHOS domains delay amyloid-ß peptide (Aß) fibril formation and reduce associated toxicity in vitro and their overexpression reduces Aß neurotoxicity in animal models of Alzheimer's disease. After intravenous administration in wild-type mice, rh Bri2, but not proSP-C, BRICHOS was detected in the brain parenchyma, suggesting that Bri2 BRICHOS selectively bypasses the blood-brain barrier (BBB). Here, our objective was to increase the brain delivery of rh proSP-C (trimer of 18 kDa subunits) and Bri2 BRICHOS (monomer to oligomer of 15 kDa subunits) using focused ultrasound combined with intravenous microbubbles (FUS + MB), which enables targeted and transient opening of the BBB. FUS + MB was targeted to one hemisphere of wild type mice and BBB opening in the hippocampal region was confirmed by magnetic resonance imaging. Two hours after FUS + MB brain histology showed no signs of tissue damage and immunohistochemistry showed abundant delivery to the brain parenchyma in 13 out of 16 cases given 10 mg/kg of proSP-C or Bri2 BRICHOS domains. The Bri2, but not proSP-C BRICHOS domain was detected also in the non-targeted hemisphere. ProSP-C and Bri2 BRICHOS domains were taken up by a subset of neurons in the hippocampus and cortex, and were detected to a minor extent in early endosomes. These results indicate that rh Bri2, but not proSP-C, BRICHOS, can be efficiently delivered into the mouse brain parenchyma and that both BRICHOS domains can be internalized by cell-specific mechanisms.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles.

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Chirp- and random-based coded ultrasonic excitation for localized blood-brain barrier opening.

Chirp- and random-based coded excitation methods have been proposed to reduce standing wave formation and improve focusing of transcranial ultrasound. However, no clear evidence has been shown to support the benefits of these ultrasonic excitation sequences in vivo. This study evaluates the chirp and periodic selection of random frequency (PSRF) coded-excitation methods for opening the blood-brain barrier (BBB) in mice. Three groups of mice (n = 15) were injected with polydisperse microbubbles and sonicated in the caudate putamen using the chirp/PSRF coded (bandwidth: 1.5­1.9 MHz, peak negative pressure: 0.52 MPa, duration: 30 s) or standard ultrasound (frequency: 1.5 MHz, pressure: 0.52 MPa, burst duration: 20 ms, duration: 5 min) sequences. T1-weighted contrast-enhanced MRI scans were performed to quantitatively analyze focused ultrasound induced BBB opening. The mean opening volumes evaluated from the MRI were mm3, mm3and mm3 for the chirp, random and regular sonications, respectively. The mean cavitation levels were V.s, V.s and V.s for the chirp, random and regular sonications, respectively. The chirp and PSRF coded pulsing sequences improved the BBB opening localization by inducing lower cavitation levels and smaller opening volumes compared to results of the regular sonication technique. Larger bandwidths were associated with more focused targeting but were limited by the frequency response of the transducer, the skull attenuation and the microbubbles optimal frequency range. The coded methods could therefore facilitate highly localized drug delivery as well as benefit other transcranial ultrasound techniques that use higher pressure levels and higher precision to induce the necessary bioeffects in a brain region while avoiding damage to the surrounding healthy tissue.

Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus.

Recombinant adeno-associated virus (rAAV) has shown great promise as a potential cure for neurodegenerative diseases. The existence of the blood-brain barrier (BBB), however, hinders efficient delivery of the viral vectors. Direct infusion through craniotomy is the most commonly used approach to achieve rAAV delivery, which carries increased risks of infection and other complications. Here, we report a focused ultrasound (FUS)-facilitated noninvasive rAAV delivery paradigm that is capable of producing targeted and neuron-specific transductions. Oscillating ultrasound contrast agents (microbubbles), driven by FUS waves, temporarily 'unlock' the BBB, allowing the systemically administrated rAAVs to enter the brain parenchyma, while maintaining their bioactivity and selectivity. Taking the advantage of the neuron-specific promoter synapsin, rAAV gene expression was triggered almost exclusively (95%) in neurons of the targeted caudate-putamen region. Both behavioral assessment and histological examination revealed no significant long-term adverse effects (in the brain and several other critical organs) for this combined treatment paradigm. Results from this study demonstrated the feasibility and safety for the noninvasive, targeted rAAV delivery, which might have open a new avenue in gene therapy in both preclinical and clinical settings.

Stochastic precision analysis of 2D cardiac strain estimation in vivo.

Ultrasonic strain imaging has been applied to echocardiography and carries great potential to be used as a tool in the clinical setting. Two-dimensional (2D) strain estimation may be useful when studying the heart due to the complex, 3D deformation of the cardiac tissue. Increasing the framerate used for motion estimation, i.e. motion estimation rate (MER), has been shown to improve the precision of the strain estimation, although maintaining the spatial resolution necessary to view the entire heart structure in a single heartbeat remains challenging at high MERs. Two previously developed methods, the temporally unequispaced acquisition sequence (TUAS) and the diverging beam sequence (DBS), have been used in the past to successfully estimate in vivo axial strain at high MERs without compromising spatial resolution. In this study, a stochastic assessment of 2D strain estimation precision is performed in vivo for both sequences at varying MERs (65, 272, 544, 815 Hz for TUAS; 250, 500, 1000, 2000 Hz for DBS). 2D incremental strains were estimated during left ventricular contraction in five healthy volunteers using a normalized cross-correlation function and a least-squares strain estimator. Both sequences were shown capable of estimating 2D incremental strains in vivo. The conditional expected value of the elastographic signal-to-noise ratio (E(SNRe|ε)) was used to compare strain estimation precision of both sequences at multiple MERs over a wide range of clinical strain values. The results here indicate that axial strain estimation precision is much more dependent on MER than lateral strain estimation, while lateral estimation is more affected by strain magnitude. MER should be increased at least above 544 Hz to avoid suboptimal axial strain estimation. Radial and circumferential strain estimations were influenced by the axial and lateral strain in different ways. Furthermore, the TUAS and DBS were found to be of comparable precision at similar MERs.

Assessment of myocardial elastography performance in phantoms under combined physiologic motion configurations with preliminary in vivo feasibility.

Myocardial elastography (ME) is a non-invasive, ultrasound-based strain imaging technique, which can detect and localize abnormalities in myocardial function. By acquiring radio-frequency (RF) frames at high frame rates, the deformation of the myocardium can be estimated, and used to identify regions of abnormal deformation indicative of cardiovascular disease. In this study, the primary objective is to evaluate the effect of torsion on the performance of ME, while the secondary objective is to image inclusions during different motion schemes. Finally, the phantom findings are validated with an in vivo human case. Phantoms of homogeneous stiffness, or containing harder inclusions, were fixed to a pump and motors, and imaged. Incremental displacements were estimated from the RF signals, and accumulated over a motion cycle, and rotation angle, radial strain and circumferential strain were estimated. Phantoms were subjected to four motion schemes: rotation, torsion, deformation, and a combination of torsion and deformation. Sonomicrometry was used as a gold standard during deformation and combined motion schemes. In the rotation scheme, the input and estimated rotation angle agree in both the homogeneous and inclusion phantoms. In the torsion scheme, the estimated rotation angle was found to be highest, closest to the source of torsion and lowest farthest from the source of torsion. In the deformation scheme, if an inclusion was not present, the estimated strain patterns accurately depicted homogeneity, while if an inclusion was present, abnormalities were observed which enabled detection of the inclusion. In addition, no significant rotation was detected. In the combined scheme, if an inclusion was not present, the estimated strain patterns accurately depicted homogeneity, while, if an inclusion was present, abnormalities were observed which enabled detection of the inclusion. Also, torsion was separated from the combined scheme and was found to be similar to the pure torsion findings. This study shows ME to be capable of accurately depicting and distinguishing between different types of motion schemes, and to be sensitive to stiffness changes in localized regions of tissue-mimicking phantoms under physiologic cardiac motion configurations, while strains estimated in the combined motion scheme were noisier than in individual motion schemes. Finally, ME was shown to be capable of distinguishing between deformation and rotation in a normal human heart in vivo.

Arterial stiffness identification of the human carotid artery using the stress-strain relationship in vivo.

Arterial stiffness is well accepted as a reliable indicator of arterial disease. Increase in carotid arterial stiffness has been associated with carotid arterial disease, e.g., atherosclerotic plaque, thrombosis, stenosis, etc. Several methods for carotid arterial stiffness assessment have been proposed. In this study, in vivo noninvasive assessment using applanation tonometry and an ultrasound-based motion estimation technique was applied in seven healthy volunteers (age 28±3.6years old) to determine pressure and wall displacement in the left common carotid artery (CCA), respectively. The carotid pressure was obtained using a calibration method by assuming that the mean and diastolic blood pressures remained constant throughout the arterial tree. The regional carotid arterial wall displacement was estimated using a 1D cross-correlation technique on the ultrasound radio frequency (RF) signals acquired at a frame rate of 505-1010Hz. Young's moduli were estimated under two different assumptions: (i) a linear elastic two-parallel spring model and (ii) a two-dimensional, nonlinear, hyperelastic model. The circumferential stress (σ(θ)) and strain (ɛ(θ)) relationship was then established in humans in vivo. A slope change in the circumferential stress-strain curve was observed and defined as the transition point. The Young's moduli of the elastic lamellae (E(1)), elastin-collagen fibers (E(2)) and collagen fibers (E(3)) and the incremental Young's moduli before ( [Formula: see text] ) and after the transition point ( [Formula: see text] ) were determined from the first and second approach, respectively, to describe the contribution of the complex mechanical interaction of the different arterial wall constituents. The average moduli E(1), E(2) and E(3) from seven healthy volunteers were found to be equal to 0.15±0.04, 0.89±0.27 and 0.75±0.29MPa, respectively. The average moduli [Formula: see text] and [Formula: see text] of the intact wall (both the tunica adventitia and tunica media layers) were found to be equal to 0.16±0.04MPa and 0.90±0.25MPa, respectively. The average moduli [Formula: see text] and [Formula: see text] of the tunica adventitia were found to be equal to 0.18±0.05MPa and 0.84±0.22MPa, respectively. The average moduli [Formula: see text] and [Formula: see text] of the tunica media were found to be equal to 0.19±0.05MPa and 0.90±0.25MPa, respectively. The stiffness of the carotid artery increased with strain during the systolic phase. In conclusion, the feasibility of measuring the regional stress-strain relationship and stiffness of the normal human carotid artery was demonstrated noninvasively in vivo.

Elevated Strain and Structural Disarray Occur at the Right Ventricular Apex.

The right ventricular apex (RVA) is a potential hot spot for development of cardiac rhythm anomalies. Many conditions, including arrhythmogenic right ventricular cardiomyopathy and Brugada's syndrome affect the RVA, and further, the RVA remains an incompletely characterized pacing region. Whether there are structural reasons underlying these conduction properties remains unsettled. In the current study, we characterize the mechanical strains and structural attributes of the right ventricular wall, and test the hypothesis that the right ventricular apex experiences heterogeneous strain distributions and altered fiber organization, and is thus susceptible to conduction alterations. Electromechanical wave imaging (EWI), or elastography, of hearts was used to quantify mechanical strains occurring through a cardiac cycle. Histological and immunofluorescence imaging techniques were used to examine cardiac wall structure and arrangement of junctional proteins. Right ventricular mechanical strains were elevated and sustained throughout systole, compared to the left ventricle and septum. Heterogeneous strain distributions, myocardial fiber disarray, and altered junctional protein localization occured at the RVA. Disarray and altered strain distributions suggest decreased structural strength at the right ventricular apex in particular and increased mechanical impositions in the right ventricle, respectively. Thus, these data demonstrate why the right ventricular apex may be particularly vulnerable to conduction abnormalities.

Non-invasive measurement of local pulse pressure by pulse wave-based ultrasound manometry (PWUM).

Central blood pressure (CBP) has been established as a relevant indicator of cardiovascular disease. Despite its significance, CBP remains particularly challenging to measure in standard clinical practice. The objective of this study is to introduce pulse wave-based ultrasound manometry (PWUM) as a simple-to-use, non-invasive ultrasound-based method for quantitative measurement of the central pulse pressure. Arterial wall displacements are estimated using radiofrequency ultrasound signals acquired at high frame rates and the pulse pressure waveform is estimated using both the distension waveform and the local pulse wave velocity. The method was tested on the abdominal aorta of 11 healthy subjects (age 35.7 ± 16 y.o.). PWUM pulse pressure measurements were compared to those obtained by radial applanation tonometry using a commercial system. The average intra-subject variability of the pulse pressure amplitude was found to be equal to 4.2 mmHg, demonstrating good reproducibility of the method. Excellent correlation was found between the waveforms obtained by PWUM and those obtained by tonometry in all subjects (0.94 < r < 0.98). A significant bias of 4.7 mmHg was found between PWUM and tonometry. PWUM is a highly translational method that can be easily integrated in clinical ultrasound imaging systems. It provides an estimate of the pulse pressure waveform at the imaged location, and may offer therefore the possibility to estimate the pulse pressure at different arterial sites. Future developments include the validation of the method against invasive estimates on patients, as well as its application to other large arteries.

Permeability assessment of the focused ultrasound-induced blood-brain barrier opening using dynamic contrast-enhanced MRI.

Focused ultrasound (FUS) in conjunction with microbubbles has been shown to successfully open the blood-brain barrier (BBB) in the mouse brain. In this study, we compute the BBB permeability after opening in vivo. The spatial permeability of the BBB-opened region was assessed using dynamic contrast-enhanced MRI (DCE-MRI). The DCE-MR images were post-processed using the general kinetic model (GKM) and the reference region model (RRM). Permeability maps were generated and the K(trans) values were calculated for a predefined volume of interest in the sonicated and the control area for each mouse. The results demonstrated that K(trans) in the BBB-opened region (0.02 +/- 0.0123 for GKM and 0.03 +/- 0.0167 min(-1) for RRM) was at least two orders of magnitude higher when compared to the contra-lateral (control) side (0 and 8.5 x 10(-4) +/- 12 x 10(-4) min(-1), respectively). The permeability values obtained with the two models showed statistically significant agreement and excellent correlation (R(2) = 0.97). At histological examination, it was concluded that no macroscopic damage was induced. This study thus constitutes the first permeability assessment of FUS-induced BBB opening using DCE-MRI, supporting the fact that the aforementioned technique may constitute a safe, non-invasive and efficacious drug delivery method.

Harmonic motion imaging for focused ultrasound (HMIFU): a fully integrated technique for sonication and monitoring of thermal ablation in tissues.

FUS (focused ultrasound), or HIFU (high-intensity-focused ultrasound) therapy, a minimally or non-invasive procedure that uses ultrasound to generate thermal necrosis, has been proven successful in several clinical applications. This paper discusses a method for monitoring thermal treatment at different sonication durations (10 s, 20 s and 30 s) using the amplitude-modulated (AM) harmonic motion imaging for focused ultrasound (HMIFU) technique in bovine liver samples in vitro. The feasibility of HMI for characterizing mechanical tissue properties has previously been demonstrated. Here, a confocal transducer, combining a 4.68 MHz therapy (FUS) and a 7.5 MHz diagnostic (pulse-echo) transducer, was used. The therapy transducer was driven by a low-frequency AM continuous signal at 25 Hz, producing a stable harmonic radiation force oscillating at the modulation frequency. A pulser/receiver was used to drive the pulse-echo transducer at a pulse repetition frequency (PRF) of 5.4 kHz. Radio-frequency (RF) signals were acquired using a standard pulse-echo technique. The temperature near the ablation region was simultaneously monitored. Both RF signals and temperature measurements were obtained before, during and after sonication. The resulting axial tissue displacement was estimated using one-dimensional cross correlation. When temperature at the focal zone was above 48 degrees C during heating, the coagulation necrosis occurred and tissue damage was irreversible. The HMI displacement profiles in relation to the temperature and sonication durations were analyzed. At the beginning of heating, the temperature at the focus increased sharply, while the tissue stiffness decreased resulting in higher HMI displacements. This was confirmed by an increase of 0.8 microm degrees C(-1)(r=0.93, p<.005). After sustained heating, the tissue became irreversibly stiffer, followed by an associated decrease in the HMI displacement (-0.79 microm degrees C(-1), r=-0.92, p<0.001). Repeated experiments showed a reproducible pattern of the HMI displacement changes with a temperature at a slope equal to 0.8+/-0.11 and -0.79+/-0.14 microm degrees C(-1), prior to and after lesion formation in seven bovine liver samples, respectively. This technique was thus capable of following the protein-denatured lesion formation based on the variation of the HMI displacements. This method could, therefore, be applied for real-time monitoring of temperature-related stiffness changes of tissues during FUS, HIFU or other thermal therapies.

Spatio-temporal analysis of molecular delivery through the blood-brain barrier using focused ultrasound.

The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 degrees C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison; 25-50 microl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 microm, scan time: 45-180 min) with gadolinium (Omniscan; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.

A novel, view-independent method for strain mapping in myocardial elastography: eliminating angle and centroid dependence.

Robust indices of regional and global cardiac function are a key factor in detection and treatment of heart disease as well as understanding of the fundamental mechanisms of a healthy heart. Myocardial elastography provides a noninvasive method for imaging and measuring displacement and strain of the myocardium for the early detection of cardiovascular disease. However, two-dimensional in-plane axial and lateral strains measured depend on the sonographic view used. This becomes especially critical in a clinical setting and may induce large variations in the measured strains, potentially leading to false diagnoses. A novel method in myocardial elastography is proposed for eliminating this view dependence by deriving the polar, principal and classified principal strains. The performance of the proposed methodology is assessed by employing 3D finite-element left-ventricular models of a control and an ischemic canine heart. Although polar strains are angle-independent, they are sensitive to the selected reference coordinate system, which requires the definition of a centroid of the left ventricle (LV). In contrast, principal strains derived through eigenvalue decomposition exhibit the inherent characteristic of coordinate system independence, offering view (i.e., angle and centroid)-independent strain measurements. Classified principal strains are obtained by assigning the principal components in the physical ventricular coordinate system. An extensive strain analysis illustrates the improvement in interpretation and visualization of the full-field myocardial deformation by using the classified principal strains, clearly depicting the ischemic and non-ischemic regions. Strain maps, independent of sonographic views and imaging planes, that can be used to accurately detect regional contractile dysfunction are demonstrated.

Elastographic Imaging of the Strain Distribution at the Anterior Cruciate Ligament and ACL-Bone Insertions.

The anterior cruciate ligament (ACL) functions as a mechanical stabilizer in the tibiofemoral joint. Over 250,000 Americans each year suffer ACL ruptures and tears, making the ACL the most commonly injured knee ligament. Methods which permit the in situ monitoring of changes in ACL graft mechanical properties during healing are needed. A long term goal in ACL reconstruction is to regenerate the ACL-bone interface. To this end, an understanding of mechanical properties of the ligament-bone interface is needed. However, experimental determination has been difficult due the small length scale (<1 mm) involved and limited resolution of standard techniques. The current study uses elastography to characterize the functional properties of the ACL and the ACL-bone interface under applied load. In a first experiment, bovine joints were excised, cast in an agar gel matrix and externally compressed. In a second experiment, tibiofemoral joints were mounted on a MTS 858 Bionix Testing System. The ACL was loaded at different strain rates and tested to failure while RF data was collected at 5 MHz. For both tensile and compression testing, axial elastograms between successive RF frames were generated using cross-correlation and recorrelation techniques. When the ACL-bone complex was tested in the tibial alignment on the MTS system, compressive strains were found to dominate at the tibial insertion. Compressive strains were observed in the ligament proper when the transducer beam was aligned with respect to the insertion during loading.

A theoretical performance assessment tool for myocardial elastography.

The main purpose of this paper is to develop a theoretical tool in order to fundamentally characterize the performance of Myocardial Elastography and identify the optimal parameters to be used for the more reliable detection of ischemia or infarction. A complete representation of the left-ventricular function throughout an entire cardiac cycle was previously demonstrated through the use of a 3D finite-element analysis (FEA) model. This FEA model together with an ultrasound image formation model is used here in order to test the performance of 2D Myocardial Elastography at distinct phases of the cardiac cycle and at different states of myocardium, i.e., normal and ischemic, based on in vivo canine data. A previously developed 3D finite-element analysis (FEA) model of a normal canine left ventricle with 80 nodes and 40 elements was used to simulate all main phases of the cardiac cycle. The axial and lateral displacements within multiple image (x-y) planes across the left-ventricular volume were iteratively calculated and corrected to reduce the decorrelation noise. Given the excellent agreement between the FEA solution and the elastographic strains measured in 2D over an entire simulated cardiac cycle, Myocardial Elastography proves to be a reliable technique for the accurate assessment of the myocardial deformation in 2D at distinct phases of the cardiac cycle as well as detection of the ischemic region. Preliminary in vivo results of a standard short-axis view in a canine myocardium are shown validating the performance assessment using the proposed model.

Quo vadis elasticity imaging?

In the past decade, an important field that has emerged as complementary to ultrasonic imaging is that of elasticity imaging. The term encompasses a variety of techniques that can depict a mechanical response or property of tissues. In ultrasound, its premise is built on two important facts: (a) that significant differences between mechanical properties of several tissue components exist and (b) that the information contained in the coherent scattering, or speckle, is sufficient to depict these differences following an external or internal mechanical stimulus. Parameters, such as velocity of vibration, displacement, strain, strain rate, velocity of wave propagation and elastic modulus, have all been demonstrated feasible in their estimation and have resulted in the accurate depiction of stiffer tissue masses, such as tumors, high-intensity focused ultrasound (HIFU) lesions and atherosclerotic plaques. More recently, through the development of ultrafast algorithms tailored to suitable hardware as well as the familiarity of the physician with the sensitivity of the methods used, one elasticity imaging technique in particular, elastography, has been shown applicable in a typical clinical ultrasound setting. In other words, elastograms can currently be obtained at quasi real-time (approximately at a frame rate of 8 frames/s) and with the use of a hand-held transducer (as opposed to the previously used frame-suspended setup) during and simultaneously with an ultrasound exam of, e.g., the breast or the prostate. The higher frame rate available with certain clinical ultrasound scanners has also resulted in the successful application of elasticity imaging techniques on the myocardium and monitoring its deformation over several cardiac cycles for the detection of ischemic regions. As a result, elasticity imaging with its ever increasing number of applications and demonstrated applicability in a typical, clinical ultrasound setting promises to make an important contribution to the ultrasound practice as we know it.

Estimating localized oscillatory tissue motion for assessment of the underlying mechanical modulus.

The technique of harmonic motion imaging (HMI) uses the localized stimulus of the oscillatory ultrasonic radiation force as produced by two overlapping beams of distinct frequencies, and estimates the resulting harmonic displacement in the tissue in order to assess its underlying mechanical properties. In this paper, we studied the relationship between measured displacement and stiffness in gels and tissues in vitro. Two focused ultrasound transducers with a 100 mm focal length were used at frequencies of 3.7500 MHz and either 3.7502 (or 3.7508 MHz), respectively, in order to produce an oscillatory motion at 200 Hz in the gel or tissue. A 1.1 MHz diagnostic transducer (Imasonics, Inc.) was also focused at 100 mm and acquired 5 ms RF signals (pulse repetition frequency (PRF)=3.5 kHz) at 100 MHz sampling frequency during radiation force application. First, three 50x50 mm(2) acrylamide gels were prepared at concentrations of 4%, 8% and 16%. The resulting displacement was estimated using crosscorrelation techniques between successively acquired RF signals with a 2 mm window and 80% window overlap at 1260 W/cm(2). A normal 1-D indentation instrument (TeMPeST) applied oscillatory loads at 0.1-200 Hz with a 5 mm-diameter flat indenter. Then, 12 displacement measurements in 6 porcine muscle specimens (two measurements/case, as above) were made in vitro, before and after ablation which was performed for 10 s at 1260 W/cm(2). In all gel cases, the harmonic displacement was found to linearly increase with intensity and exponentially decrease with gel concentration. The TeMPeST measurements showed that the elastic moduli for the 4%, 8% and 16% gels equaled 3.93+/-0.06, 17.1+/-0.2 and 75+/-2 kPa, respectively, demonstrating that the HMI displacement estimate depends directly on the gel stiffness. Finally, in the tissues samples, the mean displacement amplitude showed a twofold decrease between non-ablated and ablated tissue, demonstrating a correspondence between the HMI response and an increase in stiffness measured with the TeMPeST instrument.