Variation of ADC with Cell Cycle Phases: A Study Using Synchronized HL-60 Cells
Junzhong Xu¹, Jingping Xie¹, Jerome Jourquin², Daniel C. Colvin¹, Mark D. Does¹, Vito Quaranta², John C. Gore^1
1Institute of Imaging Science, Vanderbilt University, Nashville, TN, United States; ²Cancer Biology, Vanderbilt University, Nashville, TN, United States

Proliferating tumors usually contain a much higher fraction of cells in active cell division phases, so for a full understanding of the diffusion properties of tumors it is necessary to understand the changes that occur in cells in different phases. Here we report how oscillating gradient spin echo (OGSE) methods detect intracellular changes of synchronized HL-60 cells at different phases, while conventional pulsed gradient spin echo (PGSE) methods cannot distinguish changes at sub-cellular dimensions due to relatively long diffusion times. This feature means OGSE methods may provide extra contrast for detecting cancer.

Determining the Biophysical Mechanisms of Intracellular Water Diffusion and Its Response to Ischemia in Perfused Cell Cultures
Kevin D. Harkins^1,2, Jean-Phillipe Galons³, Joseph L. Divijak¹, Theodore P. Trouard^1,3
1Biomedical Engineering, University of Arizona, Tucson, AZ, United States; ²Vanderbilt University Institute of Image Science, Vanderbilt University, Nashville, TN, United States; ³Radiology, University of Arizona, Tucson, AZ, United States

It was initially discovered nearly two decades ago that the apparent diffusion coefficient (ADC) drops 30-50% after the onset of ischemic stroke. Despite its clinical utility, there is still no consensus on the biophysical cause of the drop in the ADC. In this work, oscillating gradient and pulsed gradient diffusion experiments were performed on perfused cell cultures to measure the ADC of intracellular water over a wide range of diffusion times. Results indicate that the biophysical mechanisms that influence ADC are diffusion time dependent, where diffusion measured at short diffusion times is highly sensitive to the intrinsic diffusion of intracellular water and the diffusion measured at longer diffusion times is more sensitive to cell size.

Acute Diffusion MRI Measurements Predict Chronic Axonal Function Assessed Using Electrophysiology
Joong Hee Kim¹, David S. K. Magnuson², Sheng-Kwei Song^1
1Radiology, Washington University , St. Louis, MO, United States; ²Neurological Surgery and Anatomical Sciences & Neurobiology, University of Louisville, Louisville, KY, United States

Diffusion tensor imaging (DTI) has been widely employed to assess central nervous system white matter integrity in animal models and patients. Herein, we demonstrate for the first time that the axonal injury marker derived by DTI as early as 3 hours post-spinal cord contusion, a time point when no existing modality is capable of assessing underlying axonal injury or the neurological disability, reflects injury severity and accurately predicts long-term neurological function.

Early Detection of Tumor Treatment Response with Temporal Diffusion Spectroscopy
Daniel C. Colvin¹, Mary E. Loveless¹, Mark D. Does¹, Zou Yue¹, Thomas E. Yankeelov¹, John C. Gore^1
1Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, United States

Temporal diffusion spectroscopy methods, which employ rapid oscillations of the motion sensitizing diffusion gradient, are capable of probing diffusion times orders of magnitude shorter than those typically achieved with conventional pulsed gradient methods.  Consequently, the apparent diffusion coefficient (ADC) measured with these methods may provide a more accurate assessment of tumor response to therapy due to their ability to detect structural variations over much shorter length scales.  Results in a 9L tumor model in rats in vivo demonstrate that these methods can detect variations in ADC within 24 hours of chemotherapeutic treatment, when conventional methods showed no such change.

Apparent Exchange Rate of Water in Human Brain Matter Revealed by a Novel Pulse Sequence
Markus Nilsson¹, Daniel Topgaard², Sara Brockstedt, Freddy Ståhlberg^1,3, Jimmy Lätt^1,4
1Department of Medical Radiation Physics, Lund University, Lund, Sweden; ²Physical Chemistry, Lund University, Lund, Sweden; ³Department of Diagnostic Radiology, Lund University, Lund, Sweden; ⁴Center for Medical Imaging and Physiology, Lund University Hospital, Lund, Sweden

Results using a novel diffusion sensitive imaging sequence generating a potentially useful contrast mechanism: the apparent exchange rate of water, related to the and cell membrane permeability. Diagnostics and prediction of treatment outcome of various pathologies might benefit from the additional information gained by knowledge of the water exchange rate. The sequence was evaluated in phantom as well as in vivo.

Neurite Beading Is Sufficient to Decrease the Apparent Diffusion Coefficient Following Ischemic Stroke
Matthew D. Budde¹, Joseph A. Frank^1
1Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD, United States

Within minutes of an ischemic stroke, the apparent diffusion coefficient (ADC) dramatically decreases in the infarcted brain tissue. Although the ADC change is likely related to cell swelling, the precise biophysical mechanism remains elusive.  In this report, it is demonstrated that swelling of axons and dendrites, collectively known as neurites, causes the cell membrane to exhibit a beaded morphology.  A simulation of diffusion in beaded neurites was performed and validated in an ex vivo model of beading in sciatic nerves.  The results demonstrate that beading of the cell membrane is sufficient to decrease ADC following acute ischemic stroke.

Accounting for Free and Restricted Diffusion Processes in Single- And Double-PFG Experiments Using a Novel Bi-Compartmental Phantom
Noam Shemesh¹, Evren Özarslan², Amnon Bar-Shir³, Peter J. Basser², Yoram Cohen^1
1School of Chemistry, Tel Aviv University, Tel Aviv, Israel; ²Section on Tissue Biophysics and Biomimetics, NICHD, National Institutes of Health, Bethesda, MD, United States; ³Chemistry Department, Tel Aviv University, Tel Aviv, Israel

White-matter voxels which are contaminated with CSF or water diffusing in perpendicular crossing fibers constitute systems in which free and restricted diffusion are superimposed. To study the microstructural information that can be obtained in such settings, we prepared a bi-compartmental phantom in which free water (Gaussian diffusion) are superimposed with water in microcapillaries (restricted diffusion). Both single- and double-PFG experiments were conducted. We find that at low q-values, the signal arising from free water masks that of restricted diffusion and that microstructural information can only be obtained at higher q-values. We also applied these findings to a crossing fibers phantom.

Feasibility of Measuring Microstructural Features of Systems with Intermediate Exchange and Sub-Cellular Compartmentalization Using Diffusion MRI - not available
Irina Kezele¹, Philip Batchelor², Cyril Poupon¹, Jean-François Mangin¹, Denis Le Bihan¹, Daniel C. Alexander^3
1NeuroSpin, CEA, Gif-sur-Yvette, France; ²King's College , London, United Kingdom; ³University College , London, United Kingdom

We propose an analytic three-compartment diffusion model where the intra-cellular architecture and exchange between the compartments are considered. This model can explain cell characteristic sizes and cell-membrane permeability, the features that are suggested to be related to different soft tissue pathologies (e.g., malignancy). Using the proposed model, we deliver an optimized imaging protocol to measure the relevant model parameters. The simulation results demonstrate the accuracy of estimating the parameters with both negligible and moderate membrane permeability, assuming pulsed-gradient spin-echo sequence and scanner parameters suitable for small animal imaging. The potential for new biomarker definition at the micro-scale is thus suggested.

Monte Carlo Study of a Two-Compartment Exchange Model of Diffusion
Els Fieremans¹, Dmitry S. Novikov¹, Jens H. Jensen¹, Joseph A. Helpern^1,2
1Radiology, New York University School of Medicine, New York, United States; ²Center for Advanced Brain Imaging, Nathan S. Kline Institute, Orangeburg, NY, United States

Chemical exchange models have been frequently applied to quantify diffusion measurement in living tissues. Here we investigate numerically a two-compartment exchange (Kärger) model as applied to diffusion in a system of parallel cylinders with permeable walls, which serves as a model for axons in white matter. We show that the Kärger model accurately predicts the diffusivity and the diffusional kurtosis when the membranes are sufficiently impermeable. The exchange time can then be derived from the time-dependence of the diffusional kurtosis. For larger permeabilities, the Kärger model overestimates the actual exchange time.

A Joint PDF for the Eigenvalues and Eigenvectors of a Diffusion Tensor
Sinisa Pajevic¹, Peter J. Basser^2
1CIT, NIH, Bethesda, MD, United States; ²NICHD, NIH, Bethesda, MD, United States

We propose a joint probability density function (pdf) of the eigensystem of a 2nd-order estimated diffusion tensor, which we show decouples into a product of  pdfs of its eigenvalues and eigenvectors for a well-designed MR experiment and moderate SNR.  This finding provides the foundation for the development of a rigorous and general statistical hypothesis-testing framework valid for measured DTI data.