Quinton W. Guerrero

Quantifying Backscatter Anisotropy Using the Reference Phantom Method

Acoustic properties can be exploited to infer and evaluate tissue microstructure. However, common assumptions are that the medium of interest is homogeneous and isotropic, and that its underlying physical properties cause diffuse scattering. In this paper, we describe how we developed and tested novel parameters designed to address isotropy/anisotropy in backscattered echo signal power in complex biological tissues. Specifically, we explored isotropy/anisotropy in backscattered power in isotropic phantoms (spherical glass beads), an anisotropic phantom (dialysis phantom with rodlike fibers), and an in vivo human tissue with well-described anisotropy (bicep muscle). Our approach uses the reference phantom method to compensate for system transfer and diffraction losses when electronically beamsteering a linear array transducer. We define three parameters to quantify the presence and orientation of anisotropic scatterers, as well as address magnitude of anisotropy. We found that these parameters can detect and sense the degree of anisotropy in backscatter in both phantoms and bicep muscle. Bias of the summary anisotropy parameters, induced through a speed of sound mismatch of sample media and reference phantom, was less than 0.2 dB if the speed of sound was within ±20 m/s of the sample media. In summary, these new parameters may be useful for testing the assumption of isotropy as well as providing more detailed information about the underlying microstructural sources of backscatter in complex biological tissues.

Quantitative ultrasound backscatter parameters in the human cervix

Quantitative ultrasound has been investigated as a tool for monitoring cervical changes that might result in preterm birth. Backscatter parameters, specifically attenuation and the backscattered power loss (BSPL), appear to be two important parameters. Sources of potential variability such as the angle of the beam interrogating the cervix, the region within the cervix, the number of previous births, and the state of ripening, have not been systematically examined, but could contribute to bias and variance in parameter estimates. Results presented here show that attenuation was affected by angle of interrogation, region in the cervix, parity, and ripened state. BSPL in the nonpregnant cervix was affected only by cervical region.

Estimation of Shear Wave Speed in the Rhesus Macaques’ Uterine Cervix

Cervical softness is a critical parameter in pregnancy. Clinically, preterm birth is associated with premature cervical softening and postdates birth is associated with delayed cervical softening. In practice, the assessment of softness is subjective, based on digital examination. Fortunately, objective, quantitative techniques to assess softness, and other parameters associated with microstructural cervical change are emerging. One of these is shear wave speed (SWS) estimation. In principle, this allows objective characterization of stiffness because waves travel more slowly in softer tissue. We are studying SWS in humans and rhesus macaques, the latter in order to accelerate translation from bench to bedside. For the current study, we estimated SWS in ex vivo cervices of rhesus macaques, n=24 nulliparous (never given birth) and n=9 multiparous (delivered at least one baby). Misoprostol (a prostaglandin used to soften human cervices prior to gynecological procedures) was administered to 13 macaques prior to necropsy (nulliparous: 7; multiparous: 6). SWS measurements were made at predetermined locations from the distal to proximal end of the cervix on both the anterior and posterior cervix, with five repeat measures at each location. The intent was to explore macaque cervical microstructure, including biological and spatial variability, to elucidate the similarities and differences between the macaque and the human cervix in order to facilitate future in vivo studies. We found that SWS is dependent on location in the normal nonpregnant macaque cervix, as in the human cervix. Unlike the human cervix, we detected no difference between ripened and unripened rhesus macaque cervix samples, nor nulliparous versus multiparous samples, although we observed a trend toward stiffer tissue in nulliparous samples. We found rhesus macaque cervix to be much stiffer than human, which is important for technique refinement. These findings are useful for guiding study of cervical microstructure in both humans and macaques.

Quantitative assessment of cervical softening during pregnancy in the Rhesus macaque with shear wave elasticity imaging

Abnormal parturition, e.g. pre- or post-term birth, is associated with maternal and neonatal morbidity and increased economic burden. This could potentially be prevented by accurate detection of abnormal softening of the uterine cervix. Shear wave elasticity imaging (SWEI) techniques that quantify tissue softness, such as shear wave speed (SWS) measurement, are promising for evaluation of the cervix. Still, interpretation of results can be complicated by biological variability (i.e. spatial variations of cervix stiffness, parity), as well as by experimental factors (i.e. type of transducer, posture during scanning). Here we investigated the ability of SWEI to detect cervical softening, as well as sources of SWS variability that can affect this task, in the pregnant and nonpregnant Rhesus macaque. Specifically, we evaluated SWS differences when imaging the cervix transabdominally with a typical linear array abdominal transducer, and transrectally with a prototype intracavitary linear array transducer. Linear mixed effects (LME) models were used to model SWS as a function of menstrual cycle day (in nonpregnant animals) and gestational age (in pregnant animals). Other variables included parity, shear wave direction, and cervix side (anterior versus posterior). In the nonpregnant cervix, the LME model indicated that SWS increased by 2% (95% confidence interval 0-3%) per day, starting eight days before menstruation. During pregnancy, SWS significantly decreased at a rate of 6% (95% CI 5-7%) per week (intracavitary approach) and 3% (95% CI 2-4%) per week (transabdominal approach), and interactions between the scanning approach and other fixed effects were also significant. These results suggest that, while absolute SWS values are influenced by factors such as scanning approach and SWEI implementation, these sources of variability do not compromise the sensitivity of SWEI to cervical softening. Our results also highlight the importance of standardizing SWEI approaches to improve their accuracy for cervical assessment.

Power Spectrum Consistency among Systems and Transducers

Use of the reference phantom method for computing acoustic attenuation and backscatter is widespread. However, clinical application of these methods has been limited by the need to acquire reference phantom data. We determined that the data acquired from 11 transducers of the same model and five clinical ultrasound systems of the same model produce equivalent estimates of reference phantom power spectra. We describe that the contribution to power spectral density variance among systems and transducers equals that from speckle variance with 59 uncorrelated echo signals. Thus, when the number of uncorrelated lines of data is small, speckle variance will dominate the power spectral density estimate variance introduced by different systems and transducers. These results suggest that, at least for this particular transducer and imaging system combination, one set of reference phantom calibration data is highly representative of the average among equivalent transducers and systems that are in good working order.

Anisotropy and Spatial Heterogeneity in Quantitative Ultrasound Parameters: Relevance to the Study of the Human Cervix

Imaging biomarkers based on quantitative ultrasound can offer valuable information about properties that inform tissue function and behavior such as microstructural organization (e.g., collagen alignment) and viscoelasticity (i.e., compliance). For example, the cervix feels softer as its microstructure remodels during pregnancy, an increase in compliance that can be objectively quantified with shear wave speed and therefore shear wave speed estimation is a potential biomarker of cervical remodeling. Other proposed biomarkers include parameters derived from the backscattered echo signal, such as attenuation and backscattered power loss, because such parameters can provide insight into tissue microstructural alignment and organization. Of these, attenuation values for the pregnant cervix have been reported, but large estimate variance reduces their clinical value. That said, parameter estimates based on the backscattered echo signal may be incorrect if assumptions they rely on, such as tissue isotropy and homogeneity, are violated. For that reason, we explored backscatter and attenuation parameters as potential biomarkers of cervical remodeling via careful investigation of the assumptions of isotropy and homogeneity in cervical tissue. Specifically, we estimated the angle- and spatial-dependence of parameters of backscattered power and acoustic attenuation in the ex vivo human cervix, using the reference phantom method and electronic steering of the ultrasound beam. We found that estimates are anisotropic and spatially heterogeneous, presumably because the tissue itself is anisotropic and heterogeneous. We conclude that appropriate interpretation of imaging biomarkers of cervical remodeling must account for tissue anisotropy and heterogeneity.

Biological factors affecting shear wave speed measurements in the Rhesus macaque non-pregnant cervix

We are studying shear wave speed (SWS) as a biomarker to detect abnormal cervical softening that could lead to spontaneous preterm birth. Elucidating factors affecting the stiffness of the in vivo non-pregnant (NP) cervix is the first step to understand the pregnant cervix. Animal models with anatomy and physiology akin to humans, such as the Rhesus macaque, can help achieve this task. Here we investigate biological and experimental factors affecting SWS estimates in the in vivo Rhesus macaque NP cervix.

Consistency of echo signal power spectra among systems and transducers

The Reference Phantom Method can be used to quantify acoustic properties of tissue by compensating for system effects using the average power spectrum from a well-characterized homogeneous medium. Widespread clinical application of the Reference Phantom Method is hindered by the need to scan the reference phantom using the same transducer, system, and system settings as used for scanning the tissue each time a new study is performed. In this investigation, we questioned the need for repeat scans of the reference phantom.

Biological and experimental factors affecting the assessment of cervical softening during pregnancy with shear wave elasticity imaging

Spontaneous preterm birth, the foremost source of neonatal mortality, could potentially be prevented by objectively detecting abnormal changes in the uterine cervix. Shear Wave Elasticity Imaging (SWEI) biomarkers can quantify cervical softening that precedes vaginal delivery. This task can be complicated by biological (i.e., heterogeneity of cervical stiffness and pregnancy history) and experimental confounders (i.e., posture during scanning). Here we investigate how these confounders influence shear wave speed (SWS) as an objective biomarker of cervical softening during pregnancy. We apply SWEI longitudinally in pregnant Rhesus macaques and compare SWS estimates from supine transabdominal (TA) and prone inter-cavitary (IC) approaches.

EP22.12: A multi-biomarker approach to evaluation of the human pregnant cervix using quantitative ultrasound (QUS) imaging biomarkers

Methods: 16 normotensive pregnant women between 24 and 40 weeks gestation with low-risk pregnancy were recruited for this study. The Samsung HS 70A ultrasound system and linear probe (L3-12A) were used by a single operator to identify a longitudinal section of the right carotid artery. A cine loop was recorded while participants were in the semi-recumbent position. CIMT was calculated using an in-built computer semi-automated programme. Measurements were repeated in each participant and the average difference was calculated. Identifying the carotid artery, obtaining a cine loop and automatically calculating IMT typically took less than a minute. No discomfort was reported by the participants. Results: Maternal CIMT values were obtained in all participants. CIMT values ranged from 0.26mm to 0.96mm. The mean difference between repeated CIMT values was 0.007mm. In our cohort CIMT did not change with increasing gestation. Conclusions: This novel semi-automated technique was able to obtain CIMT values in pregnant women rapidly. This technique can be used by a novice operator with limited technical skills and has good reproducibility. This technique may be applicable as a non-invasive bedside test for CIMT in pregnant women between 24-40 weeks gestation.