Improving contrast to noise ratio of resonance frequency contrast images (phase images) using balanced steady-state free precession
Recent MRI studies have exploited subtle magnetic susceptibility differences between brain tissues to improve anatomical contrast and resolution. These susceptibility differences lead to resonance frequency shifts which can be visualized by reconstructing the signal phase in conventional gradient echo (GRE) acquisition techniques. In this work, a method is proposed to improve the contrast to noise ratio per unit time (CNR efficiency) of anatomical MRI based on resonance frequency contrast. The method, based on the balanced steady-state free precession (bSSFP) MRI acquisition technique, was evaluated in its ability to generate contrast between gray and white matter in human brain at 3T and 7T. The results show substantially improved CNR efficiency of bSSFP phase images (2.85±0.21 times at 3 T and 1.71±0.11 times at 7 T) compared to the GRE data in a limited spatial area. This limited spatial coverage is attributed to the sensitivity of bSSFP to macroscopic B(0) inhomogeneities. With this CNR improvement, high resolution bSSFP phase images (resolution=0.3×0.3×2 mm(3), acquisition time=10min) acquired at 3T had sufficient CNR to allow the visualization of cortical laminar structures in invivo human primary visual cortex. Practical application of the proposed method may require improvement of B(0) homogeneity and stability by additional preparatory scans and/or compensation schemes such as respiration and drift compensation. Without these additions, the CNR benefits of the method may be limited to studies at low field or limited regions of interest.

title: Complex data analysis in high-resolution SSFP fMRI.
abstract: In transition-band steady-state free precession (SSFP) functional MRI (fMRI), functional contrast originates from a bulk frequency shift induced by a deoxygenated hemoglobin concentration change in the activated brain regions. This frequency shift causes a magnitude and/or phase-signal change depending on the off-resonance distribution of a voxel in the balanced-SSFP (bSSFP) profile. However, in early low-resolution studies, only the magnitude signal activations were shown. In this paper the task-correlated phase-signal change is presented in a high-resolution (1 x 1 x 1 mm3) study. To include this phase activation in a functional analysis, a new complex domain data analysis method is proposed. The results show statistically significant phase-signal changes in a large number of voxels comparable to that of the magnitude-activated voxels. The complex-data analysis method successfully includes these phase activations in the activation map and thus provides wider coverage compared to magnitude-data analysis results.

title: The contribution of myelin to magnetic susceptibility-weighted contrasts in high-field MRI of the brain
abstract: T(2)*-weighted gradient-echo MRI images at high field (≥ 7T) have shown rich image contrast within and between brain regions. The source for these contrast variations has been primarily attributed to tissue magnetic susceptibility differences. In this study, the contribution of myelin to both T(2)* and frequency contrasts is investigated using a mouse model of demyelination based on a cuprizone diet. The demyelinated brains showed significantly increased T(2)* in white matter and a substantial reduction in gray-white matter frequency contrast, suggesting that myelin is a primary source for these contrasts. Comparison of in-vivo and in-vitro data showed that, although tissue T(2)* values were reduced by formalin fixation, gray-white matter frequency contrast was relatively unaffected and fixation had a negligible effect on cuprizone-induced changes in T(2)* and frequency contrasts.

title: Sensitivity of MRI resonance frequency to the orientation of brain tissue microstructure
abstract: Recent advances in high-field (≥7 T) MRI have made it possible to study the fine structure of the human brain at the level of fiber bundles and cortical layers. In particular, techniques aimed at detecting MRI resonance frequency shifts originating from local variation in magnetic susceptibility and other sources have greatly improved the visualization of these structures. A recent theoretical study [He X, Yablonskiy DA (2009) Proc Natl Acad Sci USA 106:13558–13563] suggests that MRI resonance frequency may report not only on tissue composition, but also on microscopic compartmentalization of susceptibility inclusions and their orientation relative to the magnetic field. The proposed sensitivity to tissue structure may greatly expand the information available with conventional MRI techniques. To investigate this possibility, we studied postmortem tissue samples from human corpus callosum with an experimental design that allowed separation of microstructural effects from confounding macrostructural effects. The results show that MRI resonance frequency does depend on microstructural orientation. Furthermore, the spatial distribution of the resonance frequency shift suggests an origin related to anisotropic susceptibility effects rather than microscopic compartmentalization. This anisotropy, which has been shown to depend on molecular ordering, may provide valuable information about tissue molecular structure.

title: Respiration-induced B0 field fluctuation compensation in balanced SSFP: real-time approach for transition-band SSFP fMRI.
abstract: In functional MRI (fMRI) the resonance frequency shift induced from respiration is a major source of physiological noise. In transition-band SSFP fMRI the respiration-induced resonance offset not only increases noise interference, it also shifts the activation band. This leads to a reduction in the contrast-to-noise ratio (CNR) and the potential for varying contrast levels during the experiment. A novel real-time method that compensates for the respiration-induced resonance offset frequency is presented. This method utilizes free induction decay (FID) phase information to measure the resonance offset. For compensation, one can update the resonant frequency in real time by changing the transmit RF pulse and receiver phases to track the measured offset. The results show decreased signal power in the respiration frequency band and increased numbers of activated voxels with higher Z-scores compared to uncompensated experiments.

title: T2*-based fiber orientation mapping
abstract: Recent MRI studies at high field have observed that, in certain white matter fiber bundles, the signal in T(2)*-weighted MRI (i.e. MRI sensitized to apparent transverse relaxivity) is dependent on fiber orientation θ relative to B(0). In this study, the characteristics of this dependency are quantitatively investigated at 7 T using ex-vivo brain specimens, which allowed a large range of rotation angles to be measured. The data confirm the previously suggested variation of R(2)* (=1/T(2)*) with θ and also indicate that this dependency takes the shape of a combination of sin2θ and sin4θ functions, with modulation amplitudes (=ΔR(2)*) reaching 6.44±0.15 Hz (or ΔT(2)*=2.91±0.33 ms) in the major fiber bundles of the corpus callosum. This particular dependency can be explained by a model of local, sub-voxel scale magnetic field changes resulting from magnetic susceptibility sources that are anisotropic. As an illustration of a potential use of the orientation dependence of R(2)*, the feasibility of generating fiber orientation maps from R(2)* data is investigated.

title: Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia.
abstract: Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of 'wearing off' and dyskinaesia in Parkinson's disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until approximately 60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, L-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by L-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in L-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and 'wearing off'.

title: Estimation of anatomical locations using standard frame of reference in chest CT scans
abstract: We propose a method to establish the standard chest frame of reference (CFOR) using the rib cage in a lung CT scan. Such a reference frame is essential for referring to a certain location within a chest region and may facilitate the registration across multiple scans of a given subject as well as the comparative studies within a cohort of subjects. The robustness of the established CFOR was evaluated by estimating the anatomical locations within chest in the follow-up scan given the location in the first scan. Specifically, tracheal bifurcation point of airway tree and the center of pulmonary nodule were used as the anatomical points of interest. The CFOR was also used for exploring the spatial distribution of the anatomical location for a large number of individuals. The results show that on average the point of interest can be estimated accurately within 10.3 mm for the bifurcation point and within 12.5 mm for the pulmonary nodule’s center point. Further analyzing the spatial distribution of the CFOR coordinates across 86 subjects shows that we can localize the bifurcation point to the small subregion within the CFOR.

title: CIP2A expression is associated with synovial hyperplasia and invasive function of fibroblast-like synoviocytes in rheumatoid arthritis
abstract: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that leads to cellular proliferation in cancer cells. We aim to investigate CIP2A expression in fibroblast-like synoviocytes (FLS) and its association with the histopathological grade of synovitis and the invasive function of FLS in rheumatoid arthritis (RA). CIP2A protein expression was measured in 8 RA FLS and 8 OA FLS using Western blot analysis. CIP2A mRNA expression from 19 RA FLS and 7 OA FLS was measured using real-time PCR. Synovitis score of RA FLS-matched synovial tissues was semiquantitatively measured by two independent pathologists. An in vitro cell invasion assay was performed using RA FLS treated with CIP2A small interfering RNA (siRNA) or with control vector. Western blot analysis showed that CIP2A is more frequently overexpressed in RA FLS compared with OA FLS. CIP2A mRNA expression was higher in RA FLS compared with those in OA FLS, but did not reach statistical significance (P = 0.076). In RA, total synovitis score was strongly correlated with FLS CIP2A mRNA expression (rs = 0.849, P = 0.043). TNF-α treatment induced a robust increase in the invasive function of control FLS (P = 0.0021), but no significant effect was observed in CIP2A siRNA-treated FLS. Our data demonstrate that CIP2A expression is closely associated with the histopathological score of synovitis and invasive function of FLS in RA. These results suggest that CIP2A may play a critical role in the destructive process in RA and warrant further investigation of CIP2A as a therapeutic target.

title: Rational design, synthesis, and biological evaluation of progesterone-modified MRI contrast agents.
abstract: A series of contrast agents for magnetic resonance imaging (MRI) aimed at noninvasively determining the hormone receptor status of cancer in vitro was developed. These MRI contrast agents were prepared by conjugating progesterone to clinically used Gd(III) chelates. These agents exhibited higher progesterone receptor binding affinities in the nanomolar range and intracellular accumulation. High logP values of the modified compounds suggested that the lipophilicity of the steroid conjugates may have contributed to membrane permeability. Synchrotron radiation X-ray fluorescence microscopy and magnetic resonance images revealed that the synthesized conjugates showed the greatest cellular accumulation and significant increase in relaxivity in vitro compared to the previously developed steroid-modified agent. Transcriptional assays using the progesterone response element linked to luciferase indicated that the contrast agents entered the cell, interacted with the biological target, and drove specific progesterone-mediated transcription.

title: The use of gelatin substrates for traction force microscopy in rapidly moving cells.
abstract: The study of traction forces generated by rapidly moving cells requires the use of substrates that are highly elastic because these cells typically generate weaker traction forces than slower moving cells. Gelatin substrates are soft enough to allow deformation by rapidly moving cells such as fish epidermal keratocytes and Dictyostelium discoideum amoebas. In addition, gelatin substrates are thin (approximately 30-40 microm) and transparent, allowing them to be used in combination with high-resolution calcium imaging. Importantly, the responsiveness of gelatin substrates allows changes in traction force generation to be detected within seconds, corresponding to the timescale of calcium transients. Here we describe the manufacture and application of gelatin substrates to study the role of mechanochemical signaling in the regulation of keratocyte movement. We show how patterns of traction force generation can be analyzed from a time series of traction vector maps, and how to interpret them in relation to cell movement. In addition, we discuss how the gelatin traction force assay is being used to study the mechanics of Dictyostelium cell motility, and future applications such as the study of neuronal path finding.