Mehmet Bilgen

Phantom materials for elastography

Acoustic and mechanical properties are reported for gelatin materials used to construct tissue-like phantoms for elasticity imaging (elastography). A device and procedure for measuring elastic properties are described. The measured compression forces were comparable to results obtained from finite element analysis when linear elastic media are assumed. Also measured were the stress relaxation, temporal stability, and melting point of the materials. Aldehyde concentration was used to increase the stiffness of the gelatin by controlling the amount of collagen cross-linking. A broad range of tissue-like elastic properties was achieved with these materials, although gels continued to stiffen for several weeks. The precision for elastic modulus measurements ranged from less than 0.1% for 100 kPa samples to 8.9% for soft (<10 kPa), sticky samples.

Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential. Using in silico screening with a BDNF loop-domain pharmacophore, followed by low-throughput in vitro screening in mouse fetal hippocampal neurons, we have efficiently identified small molecules with nanomolar neurotrophic activity specific to TrkB versus other Trk family members. Neurotrophic activity was dependent on TrkB and its downstream targets, although compound-induced signaling activation kinetics differed from those triggered by BDNF. A selected prototype compound demonstrated binding specificity to the extracellular domain of TrkB. In in vitro models of neurodegenerative disease, it prevented neuronal degeneration with efficacy equal to that of BDNF, and when administered in vivo, it caused hippocampal and striatal TrkB activation in mice and improved motor learning after traumatic brain injury in rats. These studies demonstrate the utility of loop modeling in drug discovery and reveal what we believe to be the first reported small molecules derived from a targeted BDNF domain that specifically activate TrkB.We propose that these compounds constitute a novel group of tools for the study of TrkB signaling and may provide leads for developing new therapeutic agents for neurodegenerative diseases.

Deformation models and correlation analysis in elastography.

Cross-correlation functions are derived with the purpose of determining how strain inhomogeneities affect the displacement estimates used in ultrasound-based elastography. Variations in the strain profile occur in most imaging situations and are caused by fluctuations in the stress field or elastic modulus of the sample. An analytical framework for developing signal processing strategies in elastography is described, and the limitations of correlation-based methods for measuring displacements in tissuelike media caused by static compression are emphasized. This paper includes (1) an accurate approximation for an inverse coordinate transformation that release pre- and postcompression reflectivity profiles of the media, (2) a derivation of the echo-signal cross-correlation function in media with deterministic or stochastic strain profiles; (3) mathematical and graphical descriptions of the consequences that nonuniformities in the strain profile impose upon the uncertainty of displacement estimation; and (4) a demonstration of the advantages of echo signal conditioning and ultrasonic-pulse shaping to reduce the nonstationary effects that attenuate the cross-correlation peak and reduce the signal-to-noise ration for displacement estimation.

Direct strain estimation in elastography using spectral cross-correlation

Spectral estimation of tissue strain has been performed previously by using the centroid shift of the power spectrum or by estimating the variation in the mean scatterer spacing in the spectral domain. The centroid shift method illustrates the robustness of the direct, incoherent strain estimator. In this paper, we present a strain estimator that uses spectral cross-correlation of the pre- and postcompression power spectrum. The centroid shift estimator estimates strain from the mean center frequency shift, while the spectral cross-correlation estimates the shift over the entire spectrum. Spectral cross-correlation is shown to be more sensitive to small shifts in the power spectrum and, thus, provides better estimation for smaller strains when compared to the spectral centroid shift. Spectral cross-correlation shares all the advantages gained using the spectral centroid shift, in addition to providing accurate and precise strain estimation for small strains. The variance and noise properties of the spectral strain estimators quantified by their respective strain filters are also presented.

Sympathetic Hyperinnervation and Inflammatory Cell NGF Synthesis Following Myocardial Infarction in Rats

Sympathetic hyperinnervation occurs in human ventricular tissue after myocardial infarction and may contribute to arrhythmias. Aberrant sympathetic sprouting is associated with elevated nerve growth factor (NGF) in many contexts, including ventricular hyperinnervation. However, it is unclear whether cardiomyocytes or other cell types are responsible for increased NGF synthesis. In this study, left coronary arteries were ligated and ventricular tissue examined in rats 1-28 days post-infarction. Infarct and peri-infarct tissue was essentially devoid of sensory and parasympathetic nerves at all time points. However, areas of increased sympathetic nerve density were observed in the peri-infarct zone between post-ligation days 4-14. Hyperinnervation occurred in regions containing accumulations of macrophages and myofibroblasts. To assess whether these inflammatory cells synthesize NGF, sections were processed for NGF in situ hybridization and immunohistochemistry. Both macrophage1 antigen-positive macrophages and alpha-smooth muscle actin-immunoreactive myofibroblasts expressed NGF in areas where they were closely proximate to sympathetic nerves. To investigate whether NGF produced by peri-infarct cells induces sympathetic outgrowth, we co-cultured adult sympathetic ganglia with peri-infarct explants. Neurite outgrowth from sympathetic ganglia was significantly greater at post-ligation days 7-14 as compared to control tissue. Addition of an NGF function-blocking antibody prevented the increased neurite outgrowth induced by peri-infarct tissue. These findings provide evidence that inflammatory cell NGF synthesis plays a causal role in sympathetic hyperinnervation following myocardial infarction.

Multiresolution imaging in elastography

The range of strains that can be imaged by any practical elastographic imaging system is inherently limited, and a performance measure is valuable to evaluate these systems from the signal and noise properties of their output images. Such a measure was previously formulated for systems employing cross-correlation based time-delay estimators through the strain filter. While the strain filter predicts the signal-to-noise ratio (SNR/sub e/) for each tissue strain in the elastogram and provides valuable insights into the nature of image noise, it understated the effects of image resolution (axial resolution, as determined by the cross-correlation window length) on the noise. In this work, the strain filter is modified to study the strain noise at multiple resolutions. The effects of finite window length on signal decorrelation and on the variance of the strain estimator are investigated. Long-duration windows are preferred for improved sensitivity, dynamic range, and SNR/sub e/. However, in this limit the elastogram is degraded due to poor resolution. The results indicate that for nonzero strain, a window length exists at which the variance of strain estimator attains its minima, and consequently the elastographic sensitivity, dynamic range and SNR/sub e/ are strongly affected by the selected window length. Simulation results corroborate the theoretical results, illustrating the presence of a window length where the strain estimation variance is minimized for a given strain value. Multiresolution elastography, where the strain estimate with the highest SNR/sub e/ obtained by processing the pre- and post-compression waveforms at different window lengths is used to generate a composite elastogram and is proposed to improve elastograms. All the objective elastogram parameters (namely: SNR/sub e/, dynamic range, sensitivity and the average elastographic resolution-defined as the cross-correlation window length) are improved with multiresolution elastography when compared to the traditional method of utilizing a single window length to generate the elastogram. Experimental results using a phantom with a hard inclusion illustrates the improvement in elastogram obtained using multiresolution analysis.

A mouse model of sensorimotor controlled cortical impact: Characterization using longitudinal magnetic resonance imaging, behavioral assessments and histology

The present study establishes a new mouse model for traumatic brain injury (TBI), using an electromechanically driven linear motor impactor device to deliver a lateral controlled cortical impact (CCI) injury to the sensorimotor cortex. Lesion cavity size was measured, and inter-animal consistency demonstrated, at 14 days post injury. Qualitative information regarding damage progression over time was obtained by scanning with high field magnetic resonance imaging (MRI) at five time points following injury. Functional impairment and recovery were measured with the Rotarod, gridwalk and cylinder tests, and lesion cavity volume was measured post mortem with thionin-stained tissue sections. The study establishes the reliability of a linear-motor based device for producing repeatable damage in a CCI model, demonstrates the power of longitudinal MRI in studying damage evolution, and confirms that a simple battery of functional tests record sensorimotor impairment and recovery.

Dynamic contrast‐enhanced MRI of experimental spinal cord injury: In vivo serial studies

The progression of experimental spinal cord injury (SCI) was followed with in vivo dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and neurobehavioral studies on postinjury days 0, 2, 4, 7, 10, 14, 17, 21, 28, 35, and 42. Gadopentate dimeglumine (Gd) was administered IV and postcontrast, T1‐weighted, axial images were acquired repetitively for up to 60 min. Images were analyzed to determine the spatial and temporal evolution of the intensity enhancement. A statistical decision mechanism was developed to objectively detect the enhancement. Strong and rapid enhancement was observed at the epicenter of injury, indicating a significant compromise in blood spinal cord barrier. The enhanced regions in each slice were combined to estimate the area and volume of the lesion. On the day of injury, around 85% of the total cord area at the epicenter showed enhancement within the first 15 min of Gd administration. At the same time, the enhanced volumes attained nearly 40% of the total cord volume and extended axially over 8 mm along the cord. These quantities decreased steadily with time, with a concomitant improvement in the motor functions. The volume of enhancement correlated highly with the neurobehavioral tests (r = –0.87). DCE‐MRIs revealed small hyperintense regions distributed inside white matter about two weeks postinjury. Based on histology, these enhancements appear to represent new vessels with “leaky endothelium.” Magn Reson Med 45:614–622, 2001.

The nonstationary strain filter in elastography: Part II. Lateral and elevational decorrelation

The nonstationary evolution of the strain filter due to lateral and elevational motion of the tissue scatterers across the ultrasound beam is analyzed for the 1-D cross-correlation-based strain estimator. The effective correlation coefficient that includes the contributions due to lateral and elevational signal decorrelation is used to derate the upper bound of the signal-to-noise ratio in the elastogram (SNRe) predicted by the ideal strain filter. In the case of an elastically homogeneous target, if the transducer is on the axis of symmetry of such target in the elevational direction, the motion of the scatterers out the imaging plane is minimized. In addition, the ultrasound beam along the elevational direction is broader, allowing scatterers to stay longer within the beam during tissue compression. Under these conditions, lateral signal decorrelation becomes the primary contributor to the nonstationary behavior of the strain filter. Both the elastographic SNRe and the dynamic range are reduced, with an increase in lateral decorrelation. Finite element simulations and phantom experiments are presented in this paper to corroborate the theoretical strain filter. The nonstationary behavior of the strain filter is reduced by confining the tissue in the lateral direction (minimizing motion of tissue scatterers), thereby improving the quality of the elastogram.

Elastostatics of a spherical inclusion in homogeneous biological media

A three-dimensional spherical inclusion model that approximates a lesion bonded to a tissue matrix is proposed for biomedical elastography. Analytical formulae describing spatial strain and stress distributions generated in infinite media by uniform loading are given under a linear, homogeneous, isotropic elasticity assumption. Strain and stress distributions are also calculated using finite-element analysis (FEA) for a variety of cases to determine the effects of shear modulus distribution, external loading conditions (uniform stress versus uniform displacement), compressor size and matrix dimensions on the elastostatics of the tissue. Analytical strain and stress predictions are shown to agree with the FEA results to within 10% accuracy provided that the matrix dimensions are at least ten times that of the inclusion. Also for these cases, uniform-stress boundary conditions can be equivalently represented by uniform displacement of the boundary. Spherical inclusions exhibit a lower efficiency for transferring elastic shear modulus contrast into strain contrast than cylindrical or planar inclusions. Additional compression will increase the strain contrast. However, large compressions also lead to increases in ultrasonic signal decorrelation and strain and stress concentrations in the homogeneous matrix around the inclusion. Although strain concentrations may help describe the boundaries of the inclusion more clearly, they also increase the risk of damaging the tissue. Understanding the strain and stress distributions in a biological tissue containing a lesion is necessary for optimizing the experimental configurations and consequently improving the diagnostic values of elasticity imaging.