1-Norm waveform analysis for MR elastography-based quantification of inhomogeneity: Effects of the freeze-thaw cycle and Alzheimer's disease.

BACKGROUND: Despite its success in the mechanical characterization of biological tissues, magnetic resonance elastography (MRE) uses ill-posed wave inversions to estimate tissue stiffness. 1-Norm has been recently introduced as a mathematical measure for the scattering of mechanical waves due to inhomogeneities based on an analysis of the delineated contours of wave displacement. PURPOSE: To investigate 1-Norm as an MRE-based quantitative biomarker of mechanical inhomogeneities arising from microscopic structural tissue alterations caused by the freeze-thaw cycle (FTC) or Alzheimer's disease (AD). METHODS: In this proof-of-concept study, we prospectively investigated excised porcine kidney (n = 6), liver (n = 6), and muscle (n = 6) before vs. after the FTC at 500-2000 Hz and excised murine brain of healthy controls (n = 3) vs. 5xFAD species with AD (n = 3) at 1200-1800 Hz using 0.5 T tabletop MRE. 1-Norm analysis was compared with conventional wave inversion. RESULTS: While the FTC reduced both stiffness and inhomogeneity in kidney, liver, and muscle tissue, AD led to lower brain stiffness but more pronounced mechanical inhomogeneity. CONCLUSION: Our preliminary results show that 1-Norm is sensitive to tissue mechanical inhomogeneity due to FTC and AD without relying on ill-posed wave inversion techniques. 1-Norm has the potential to be used as an MRE-based diagnostic biomarker independent of stiffness to characterize abnormal conditions that involve changes in tissue mechanical inhomogeneity.

Quantifying uniaxial prestress and waveguide effects on dynamic elastography estimates for a cylindrical rod.

Dynamic elastography attempts to reconstruct quantitative maps of the viscoelastic properties of materials by noninvasively measuring mechanical wave motion in them. The target motion is typically transversely-polarized relative to the wave propagation direction, such as bulk shear wave motion. In addition to neglecting waveguide effects caused by small lengths in one dimension or more, many reconstruction strategies also ignore nonzero, non-isotropic static preloads. Significant anisotropic prestress is inherent to the functional role of some biological materials of interest, which also are small in size relative to shear wavelengths in one or more dimensions. A cylindrically shaped polymer structure with isotropic material properties is statically elongated along its axis while its response to circumferentially-, axially-, and radially-polarized vibratory excitation is measured using optical or magnetic resonance elastography. Computational finite element simulations augment and aid in the interpretation of experimental measurements. We examine the interplay between uniaxial prestress and waveguide effects. A coordinate transformation approach previously used to simplify the reconstruction of un-prestressed transversely isotropic material properties based on elastography measurements is adapted with partial success to estimate material viscoelastic properties and prestress conditions without requiring advanced knowledge of either.

Decoupling Uniaxial Tensile Prestress and Waveguide Effects From Estimates of the Complex Shear Modulus in a Cylindrical Structure Using Transverse-Polarized Dynamic Elastography.

Dynamic elastography, whether based on magnetic resonance, ultrasound, or optical modalities, attempts to reconstruct quantitative maps of the viscoelastic properties of biological tissue, properties altered by disease and injury, by noninvasively measuring mechanical wave motion in the tissue. Most reconstruction strategies that have been developed neglect boundary conditions, including quasi-static tensile or compressive loading resulting in a nonzero prestress. Significant prestress is inherent to the functional role of some biological tissues currently being studied using elastography, such as skeletal and cardiac muscle, arterial walls, and the cornea. In the present article a configuration, inspired by muscle elastography but generalizable to other applications, is analytically and experimentally studied. A hyperelastic polymer phantom cylinder is statically elongated in the axial direction while its response to transverse-polarized vibratory excitation is measured. We examine the interplay between uniaxial prestress and waveguide effects in this muscle-like tissue phantom using computational finite element simulations and magnetic resonance elastography measurements. Finite deformations caused by prestress coupled with waveguide effects lead to results that are predicted by a coordinate transformation approach that has been previously used to simplify reconstruction of anisotropic properties using elastography. Here, the approach estimates material viscoelastic properties that are independent of the nonhomogeneous prestress conditions without requiring advanced knowledge of those stress conditions.

The combined importance of finite dimensions, anisotropy, and pre-stress in acoustoelastography.

Dynamic elastography, whether based on magnetic resonance, ultrasound, or optical modalities, attempts to reconstruct quantitative maps of the viscoelastic properties of biological tissue, properties that are altered by disease and injury, by noninvasively measuring mechanical wave motion in the tissue. Most reconstruction strategies that have been developed neglect boundary conditions, including quasistatic tensile or compressive loading resulting in a nonzero prestress. Significant prestress is inherent to the functional role of some biological tissues currently being studied using elastography, such as skeletal and cardiac muscle, arterial walls, and the cornea. In the present article, we review how prestress alters both bulk mechanical wave motion and wave motion in one- and two-dimensional waveguides. Key findings are linked to studies on skeletal muscle and the human cornea, as one- and two-dimensional waveguide examples. This study highlights the underappreciated combined acoustoelastic and waveguide challenge to elastography. Can elastography truly determine viscoelastic properties of a material when what it is measuring is affected by both these material properties and unknown prestress and other boundary conditions?

Optical coherence elastography for assessing the influence of intraocular pressure on elastic wave dispersion in the cornea.

The cornea is a highly specialized organ that relies on its mechanical stiffness to maintain its aspheric geometry and refractive power, and corneal diseases such as keratoconus have been linked to abnormal tissue stiffness and biomechanics. Dynamic optical coherence elastography (OCE) is a clinically promising non-contact and non-destructive imaging technique that can provide measurements of corneal tissue stiffness directly in vivo. The method relies on the concepts of elastography where shear waves are generated and imaged within a tissue to obtain mechanical properties such as tissue stiffness. The accuracy of OCE-based measurements is ultimately dependent on the mathematical theories used to model wave behavior in the tissue of interest. In the cornea, elastic waves propagate as guided wave modes which are highly dispersive and can be mathematically complex to model. While recent groups have developed detailed theories for estimating corneal tissue properties from guided wave behavior, the effects of intraocular pressure (IOP)-induced prestress have not yet been considered. It is known that prestress alone can strongly influence wave behavior, in addition to the associated non-linear changes in tissue properties. This present study shows that failure to account for the effects of prestress may result in overestimations of the corneal shear moduli, particularly at high IOPs. We first examined the potential effects of IOP and IOP-induced prestress using a combination of approximate mathematical theories describing wave behavior in thin plates with observations made from data published in the OCE literature. Through wave dispersion analysis, we deduce that IOP introduces a tensile hoop stress and may also influence an elastic foundational effect that were observable in the low-frequency components of the dispersion curves. These effects were incorporated into recently developed models of wave behavior in nearly incompressible, transversely isotropic (NITI) materials. Fitting of the modified NITI model with ex vivo porcine corneal data demonstrated that incorporation of the effects of IOP resulted in reduced estimates of corneal shear moduli. We believe this demonstrates that overestimation of corneal stiffness occurs if IOP is not taken into consideration. Our work may be helpful in separating inherent corneal stiffness properties that are independent of IOP; changes in these properties and in IOP are distinct, clinically relevant issues that affect the cornea health.

Axially- and torsionally-polarized radially converging shear wave MRE in an anisotropic phantom made via Embedded Direct Ink Writing.

Magnetic Resonance Elastography (MRE) is a non-invasive imaging method to quantitatively map the shear viscoelastic properties of soft tissues. In this study, Embedded Direct Ink Writing is used to fabricate a muscle mimicking anisotropic phantom that may serve as a standard for imaging studies of anisotropic materials. The technique allowed us to obtain a long shelf life silicone-based phantom expressing transverse isotropic mechanical properties. Another goal of the present investigation is to introduce a torsionally-polarized, radially-converging shear wave actuation method for MRE. The implemented design for this novel setup was first validated via its application to isotropic and homogeneous gelatin phantoms. Then, a comparison of the resulting complex wave images from axially- and torsionally-polarized MRE on the developed anisotropic phantom and on a skeletal muscle murine sample is presented, highlighting the value of using multiple actuation and motion encoding polarization directions when studying anisotropic materials.

Toward a model-based patient selection strategy for proton therapy: External validation of photon-derived normal tissue complication probability models in a head and neck proton therapy cohort.

OBJECTIVE: To externally validate head and neck cancer (HNC) photon-derived normal tissue complication probability (NTCP) models in patients treated with proton beam therapy (PBT). METHODS: This prospective cohort consisted of HNC patients treated with PBT at a single institution. NTCP models were selected based on the availability of data for validation and evaluated by using the leave-one-out cross-validated area under the curve (AUC) for the receiver operating characteristics curve. RESULTS: 192 patients were included. The most prevalent tumor site was oropharynx (n=86, 45%), followed by sinonasal (n=28), nasopharyngeal (n=27) or parotid (n=27) tumors. Apart from the prediction of acute mucositis (reduction of AUC of 0.17), the models overall performed well. The validation (PBT) AUC and the published AUC were respectively 0.90 versus 0.88 for feeding tube 6months PBT; 0.70 versus 0.80 for physician-rated dysphagia 6months after PBT; 0.70 versus 0.68 for dry mouth 6months after PBT; and 0.73 versus 0.85 for hypothyroidism 12months after PBT. CONCLUSION: Although a drop in NTCP model performance was expected for PBT patients, the models showed robustness and remained valid. Further work is warranted, but these results support the validity of the model-based approach for selecting treatment for patients with HNC.

Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer - A case matched analysis.

BACKGROUND: Owing to its physical properties, intensity-modulated proton therapy (IMPT) used for patients with oropharyngeal carcinoma has the ability to reduce the dose to organs at risk compared to intensity-modulated radiotherapy (IMRT) while maintaining adequate tumor coverage. Our aim was to compare the clinical outcomes of these two treatment modalities. METHODS: We performed a 1:2 matching of IMPT to IMRT patients. Our study cohort consisted of IMPT patients from a prospective quality of life study and consecutive IMRT patients treated at a single institution during the period 2010-2014. Patients were matched on unilateral/bilateral treatment, disease site, human papillomavirus status, T and N status, smoking status, and receipt of concomitant chemotherapy. Survival analyzes were performed using a Cox model and binary toxicity endpoints using a logistic regression analysis. RESULTS: Fifty IMPT and 100 IMRT patients were included. The median follow-up time was 32months. There were no imbalances in patient/tumor characteristics except for age (mean age 56.8years for IMRT patients and 61.1years for IMPT patients, p-value=0.010). Statistically significant differences were not observed in overall survival (hazard ratio (HR)=0.55; 95% confidence interval (CI): 0.12-2.50, p-value=0.44) or in progression-free survival (HR=1.02; 95% CI: 0.41-2.54; p-value=0.96). The age-adjusted odds ratio (OR) for the presence of a gastrostomy (G)-tube during treatment for IMPT vs IMRT were OR=0.53; 95% CI: 0.24-1.15; p-value=0.11 and OR=0.43; 95% CI: 0.16-1.17; p-value=0.10 at 3months after treatment. When considering the pre-planned composite endpoint of grade 3 weight loss or G-tube presence, the ORs were OR=0.44; 95% CI: 0.19-1.0; p-value=0.05 at 3months after treatment and OR=0.23; 95% CI: 0.07-0.73; p-value=0.01 at 1year after treatment. CONCLUSION: Our results suggest that IMPT is associated with reduced rates of feeding tube dependency and severe weight loss without jeopardizing outcome. Prospective multicenter randomized trials are needed to validate such findings.

Immediate Epileptogenesis after Kainate-Induced Status Epilepticus in C57BL/6J Mice: Evidence from Long Term Continuous Video-EEG Telemetry.

The C57BL/6J mouse as a model of seizure/epilepsy is challenging due to high mortality and huge variability in response to kainate. We have recently demonstrated that repeated administration of a low dose of kainate by intraperitoneal route can induce severe status epilepticus (SE) with 94% survival rate. In the present study, based on continuous video-EEG recording for 4-18 weeks from epidurally implanted electrodes on the cortex, we demonstrate that this method also induces immediate epileptogenesis (<1-5 days post-SE). This finding was based on identification of two types of spontaneous recurrent seizures; behavioral convulsive seizures (CS) and electrographic nonconvulsive seizures (NCS). The identification of the spontaneous CS, stage 3-5 types, was based on the behaviors (video) that were associated with the EEG characteristics (stage 3-5 epileptiform spikes), the power spectrum, and the activity counts. The electrographic NCS identification was based on the stage 1-2 epileptiform spike clusters on the EEG and their associated power spectrum. Severe SE induced immediate epileptogenesis in all the mice. The maximum numbers of spontaneous CS were observed during the first 4-6 weeks of the SE and they decreased thereafter. Mild SE also induced immediate epileptogenesis in some mice but the CS were less frequent. In both the severe and the mild SE groups, the spontaneous electrographic NCS persisted throughout the 18 weeks observation period, and therefore this could serve as a chronic model for complex seizures. However, unlike rat kainate models, the C57BL/6J mouse kainate model is a unique regressive CS model of epilepsy. Further studies are required to understand the mechanism of recovery from spontaneous CS in this model, which could reveal novel therapeutic targets for epilepsy.