Greg J. Stanisz

Tracking oxygen effects on MR signal in blood and skeletal muscle during hyperoxia exposure

Blood and muscle T1 and T2 relaxivity was examined under normoxic (air; 20.8% O2) and hyperoxic (100% O2) conditions to determine whether the oxygenation state of blood in the large vessels and in the microcirculation can be monitored in vivo. The femoral artery/vein and the soleus and gastrocnemius muscles were examined in healthy human male volunteers. Arterial blood T1 decreased with hyperoxia, while venous blood T2 increased, due to increased dissolved O2 and decreased deoxyhemoglobin, respectively. A biexponential T2 model of muscle is proposed, where the short T2 component reflects primarily the intracellular and interstitial compartments (in fast exchange), and the long T2 reflects blood. In this model, the long T2 component increased with hyperoxia exposure. This was more evident in slow twitch (soleus) than in fast twitch (gastrocnemius) muscle. It is concluded that changes in the long T2 component reflect change in the microcirculation oxygenation state. J. Magn. Reson. Imaging 1999;9:814–820.

Cellular-interstitial water exchange and its effect on the determination of contrast agent concentration in vivo: Dynamic contrast-enhanced MRI of human internal obturator muscle

The purpose of this study was to assess the effects of cellular‐interstitial water exchange on estimates of tracer kinetics parameters obtained using rapid dynamic contrast‐enhanced (DCE) MRI. Data from the internal obturator muscle of six patients were examined using three models of water exchange: no exchange (NX), fast exchange limit (FXL), and intermediate rate (shutter‐speed [SS]). In combination with additional multiple flip angle (FA) data, a full two‐pool exchange model was also used. The results obtained using the NX model (transfer constant, Ktrans = 0.049 ± 0.027 min–1, apparent interstitial volume, ve = 0.14 ± 0.04) were marginally higher than those obtained using the FXL model (Ktrans = 0.045 ± 0.025 min–1, ve = 0.13 ± 0.04), but the error bars overlapped in two‐thirds of these parameter estimate pairs. Estimates of Ktrans and ve obtained using the SS model exceeded those obtained using the NX model in half the patients, and many estimates, including all those of intracellular residence time of water, ti, were imprecise. Results obtained using the full two‐pool model fell between those obtained using FXL and NX models, and estimates of ti were also imprecise. The results suggest that data obtained using clinically relevant DCE‐MRI are exchange‐insensitive and unsuitable for the assessment of cellular‐interstitial water exchange. Magn Reson Med 60:1011–1019, 2008.

The effects of intrathecal injection of a hyaluronan-based hydrogel on inflammation, scarring and neurobehavioural outcomes in a rat model of severe spinal cord injury associated with arachnoiditis

Traumatic spinal cord injury (SCI) comprises a heterogeneous condition caused by a complex array of mechanical forces that damage the spinal cord - making each case somewhat unique. In addition to parenchymal injury, a subset of patients experience severe inflammation in the subarachnoid space or arachnoiditis, which can lead to the development of fluid-filled cavities/syringes, a condition called post-traumatic syringomyelia (PTS). Currently, there are no therapeutic means to address this devastating complication in patients and furthermore once PTS is diagnosed, treatment is often prone to failure. We hypothesized that reducing subarachnoid inflammation using a novel bioengineered strategy would improve outcome in a rodent model of PTS. A hydrogel of hyaluronan and methyl cellulose (HAMC) was injected into the subarachnoid space 24 h post PTS injury in rats. Intrathecal injection of HAMC reduced the extent of fibrosis and inflammation in the subarachnoid space. Furthermore, HAMC promoted improved neurobehavioural recovery, enhanced axonal conduction and reduced the extent of the lesion as assessed by MRI and histomorphometric assessment. These findings were additionally associated with a reduction in the post-traumatic parenchymal fibrous scar formation as evidenced by reduced CSPG deposition and reduced IL-1α cytokine levels. Our data suggest that HAMC is capable of modulating inflammation and scarring events, leading to improved functional recovery following severe SCI associated with arachnoiditis.

Optimizing T1-weighted imaging of cortical myelin content at 3.0 T

With increases in the sensitivity and resolution of anatomical MRI for the brain, methods for mapping the organization of the cerebral cortex by imaging its myelin content have emerged. This identifies major sensory and motor regions and could be used in studies of cortical organization, particularly if patterns of myelination can be visualized over the cortical surface robustly in individual subjects. The imaging problem is difficult, however, because of the relative thinness of the cerebral cortex and the low intracortical tissue contrast. In this paper, we optimize the contrast of T(1)-weighted MRI to help better visualize patterns of myelination. We measure a small but statistically significant difference in T(1) of 171 ± 40 ms between cortical regions with low and high myelin contents in the human cortex at 3T, and then perform simulations to choose parameters for an inversion-recovery pulse sequence that utilizes this T(1) difference to increase contrast within the cortex. We show that lengthening the delay between signal acquisition and the next inversion pulse in the sequence increases intracortical contrast more effectively than does image averaging. Using the optimized sequence, we show that major myelinated regions that are relatively thick, such as the primary motor and auditory regions, can be visualized well in individuals at 3T using whole-cortex 3D images made at 1mm isotropic resolution, while thinner regions, such as the primary visual cortex, can be visualized using targeted 3D images made at 0.5mm isotropic resolution. Our findings demonstrate that patterns of myelination can be better visualized in individual subjects when the imaging is optimized to highlight intracortical contrast and can help to pave the way for the creation of matched maps of microanatomy and function in the cortex of living individual humans.

Magnetic resonance microscopy of human and porcine neurons and cellular processes.

With its unparalleled ability to safely generate high-contrast images of soft tissues, magnetic resonance imaging (MRI) has remained at the forefront of diagnostic clinical medicine. Unfortunately due to resolution limitations, clinical scans are most useful for detecting macroscopic structural changes associated with a small number of pathologies. Moreover, due to a longstanding inability to directly observe magnetic resonance (MR) signal behavior at the cellular level, such information is poorly characterized and generally must be inferred. With the advent of the MR microscope in 1986 came the ability to measure MR signal properties of theretofore unobservable tissue structures. Recently, further improvements in hardware technology have made possible the ability to visualize mammalian cellular structure. In the current study, we expand upon previous work by imaging the neuronal cell bodies and processes of human and porcine α-motor neurons. Complimentary imaging studies are conducted in pig tissue in order to demonstrate qualitative similarities to human samples. Also, apparent diffusion coefficient (ADC) maps were generated inside porcine α-motor neuron cell bodies and portions of their largest processes (mean=1.7 ± 0.5 μm²/ms based on 53 pixels) as well as in areas containing a mixture of extracellular space, microvasculature, and neuropil (0.59 ± 0.37 μm²/ms based on 33 pixels). Three-dimensional reconstruction of MR images containing α-motor neurons shows the spatial arrangement of neuronal projections between adjacent cells. Such advancements in imaging portend the ability to construct accurate models of MR signal behavior based on direct observation and measurement of the components which comprise functional tissues. These tools would not only be useful for improving our interpretation of macroscopic MRI performed in the clinic, but they could potentially be used to develop new methods of differential diagnosis to aid in the early detection of a multitude of neuropathologies.

MRI as a tool for evaluation of oral controlled release dosage forms.

The magnetic resonance imaging (MRI) studies of controlled-release (CR) dosage forms can be roughly divided into two groups. The first comprises studies performed in static conditions (small solvent volumes and ambient temperature). Such studies have provided insight into molecular phenomena in hydrating polymeric matrices. The second group covers research performed in dynamic conditions (medium flow or stirring) related to drug dissolution. An important issue is supplementation of the MRI results with data obtained by complementary techniques, such as X-ray microtomography (μCT). As we discuss here, an understanding of the mechanism underlying the release of the drug from the dosage form will lead to the development of detailed, molecularly defined, CR dosage forms.

A novel method for simultaneous 3D B1 and T1 mapping: the method of slopes (MoS)

A novel three‐dimensional simultaneous B1 and T1 mapping method is introduced: the method of slopes (MoS). The linearity of the spoiled gradient recalled echo (SPGR) signal vs flip angle relation is exploited: B1 mapping is achieved by a two‐point extrapolation to signal null with a correction scheme while T1 mapping uses the slopes of the SPGR signal vs flip angle curves near the origin and near the signal null. This new method improves upon the existing variable flip angle (VFA) T1‐mapping method in that (i) consistency between B1 and T1 maps is ensured (ii) the sampling scheme is T1‐independent (iii) the noise bias and singularity, associated with using a linear form for the SPGR signal equation, is eliminated by using the full equation. The method is shown to yield accurate and robust results via simulations. Initial estimates of B1 and T1 values are obtained from three data points via simple computations and straight line approximations. Initial estimates of B1 values, for a range of values, are shown to be accurate due to the proposed B1 correction scheme. The accuracy and robustness of T1 values is achieved via a non‐linear fitting algorithm which includes a fourth data point sampled at high SNR. The MoS was validated by comparing resulting B1 and T1 maps with those obtained using other standard methods. Finally, the ability to obtain brain B1 and T1 maps using the MoS was demonstrated by in vivo experiments. The MoS is expected to perform well on other motion‐free anatomical regions as well. Copyright

An in vivo model of anti-inflammatory activity of subdural dexamethasone following the spinal cord injury

Current therapies to limit the neural tissue destruction following the spinal cord injury are not effective. Our recent studies indicate that the injury to the white matter of the spinal cord results in a severe inflammatory response where macrophages phagocytize damaged myelin and the fluid-filled cavity of injury extends in size with concurrent and irreversible destruction of the surrounding neural tissue over several months. We previously established that a high dose of 4mg/rat of dexamethasone administered for 1 week via subdural infusion remarkably lowers the numbers of infiltrating macrophages leaving large amounts of un-phagocytized myelin debris and therefore inhibits the severity of inflammation and related tissue destruction. But this dose was potently toxic to the rats. In the present study the lower doses of dexamethasone, 0.125-2.0mg, were administered via the subdural infusion for 2 weeks after an epidural balloon crush of the mid-thoracic spinal cord. The spinal cord cross-sections were analyzed histologically. Levels of dexamethasone used in the current study had no systemic toxic effect and limited phagocytosis of myelin debris by macrophages in the lesion cavity. The subdural infusion with 0.125-2.0mg dexamethasone over 2 week period did not eliminate the inflammatory process indicating the need for a longer period of infusion to do so. However, this treatment has probably lead to inhibition of the tissue destruction by the severe, prolonged inflammatory process.

The origins of breast cancer associated with mammographic density: a testable biological hypothesis

BackgroundOur purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases.MethodsWe used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population.ResultsExtensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population.ConclusionsThese findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions.

A realistic phantom for validating MRI‐based synthetic CT images of the human skull

Purpose To introduce a new realistic human skull phantom for the validation of synthetic CT images of cortical bone from ultra‐short echo‐time (UTE) sequences. Methods A human skull of an adult female was utilized as a realistic representation of skull cortical bone. The skull was stabilized in a special acrylic container and was filled with contrast agents that have T1 and T2 relaxation times similar to human brain. The phantom was MR scanned at 3T with UTE and T2‐weighted sequences, followed by CT. A clustering approach was developed to extract the cortical bone signal from MR images. Symbol maps of the skull were calculated. Synthetic CT images of the bone were compared to cortical bone signal extracted from CT images and confounding factors, such as registration errors, were analyzed. Symbol. No Caption available. Results Dice similarity coefficient (DSC) of UTE‐detected cortical bone was 0.84 and gradually decreased with decreasing number of spokes. DSC did not significantly depend on echo‐time. Registration errors were found to be significant confounding factors, with 25% decrease in DSC for consistent 2 mm error at each axis. Conclusion This work introduced a new realistic human skull phantom, specifically for the evaluation and analysis of synthetic CT images of cortical bone.