Animal Magnetic Resonance Imaging System Research Articles

Magnetic Resonance Electrical Properties Tomography Based on Modified Physics-Informed Neural Network and Multiconstraints.

This paper presents a novel method based on leveraging physics-informed neural networks for magnetic resonance electrical property tomography (MREPT). MREPT is a noninvasive technique that can retrieve the spatial distribution of electrical properties (EPs) of scanned tissues from measured transmit radiofrequency (RF) in magnetic resonance imaging (MRI) systems. The reconstruction of EP values in MREPT is achieved by solving a partial differential equation derived from Maxwell's equations that lacks a direct solution. Most conventional MREPT methods suffer from artifacts caused by the invalidation of the assumption applied for simplification of the problem and numerical errors caused by numerical differentiation. Existing deep learning-based (DL-based) MREPT methods comprise data-driven methods that need to collect massive datasets for training or model-driven methods that are only validated in trivial cases. Hence we proposed a model-driven method that learns mapping from a measured RF, its spatial gradient and Laplacian to EPs using fully connected networks (FCNNs). The spatial gradient of EP can be computed through the automatic differentiation of FCNNs and the chain rule. FCNNs are optimized using the residual of the central physical equation of convection-reaction MREPT as the loss function (L). To alleviate the ill condition of the problem, we added multiconstraints, including the similarity constraint between permittivity and conductivity and the ℓ1 norm of spatial gradients of permittivity and conductivity, to the L. We demonstrate the proposed method with a three-dimensional realistic head model, a digital phantom simulation, and a practical phantom experiment at a 9.4T animal MRI system.

Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy

IntroductionConventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI). Materials and methodsMice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi-tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology. Results and discussionsAll treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment.

Assessment of Transarterial Chemoembolization Using Super-resolution Ultrasound Imaging and a Rat Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly prevalent form of liver cancer diagnosed annually in 600,000 people worldwide. A common treatment is transarterial chemoembolization (TACE), which interrupts the blood supply of oxygen and nutrients to the tumor mass. The need for repeat TACE treatments may be assessed in the weeks after therapy with contrast-enhanced ultrasound (CEUS) imaging. Although the spatial resolution of traditional CEUS has been restricted by the diffraction limit of ultrasound (US), this physical barrier has been overcome by a recent innovation known as super-resolution US (SRUS) imaging. In short, SRUS enhances the visible details of smaller microvascular structures on the 10 to 100 µm scale, which unlocks a host of new clinical opportunities for US. In this study, a rat model of orthotopic HCC is introduced and TACE treatment response (to a doxorubicin-lipiodol emulsion) is assessed using longitudinal SRUS and magnetic resonance imaging (MRI) performed at 0, 7 and 14 d. Animals were euthanized at 14 d for histological analysis of excised tumor tissue and determination of TACE response, that is, control, partial response or complete response. CEUS imaging was performed using a pre-clinical US system (Vevo 3100, FUJIFILM VisualSonics Inc.) equipped with an MX201 linear array transducer. After administration of a microbubble contrast agent (Definity, Lantheus Medical Imaging), a series of CEUS images were collected at each tissue cross-section as the transducer was mechanically stepped at 100 μm increments. SRUS images were formed at each spatial position, and a microvascular density metric was calculated. Microscale computed tomography (microCT, OI/CT, MILabs) was used to confirm TACE procedure success, and tumor size was monitored using a small animal MRI system (BioSpec 3T, Bruker Corp.). Although there were no differences at baseline (p > 0.15), both microvascular density levels and tumor size measures from the complete responder cases at 14 d were considerably lower and smaller, respectively, than those in the partial responder or control group animals. Histological analysis revealed tumor-to-necrosis levels of 8.4%, 51.1% and 100%, for the control, partial responder and complete responder groups, respectively (p < 0.005). SRUS imaging is a promising modality for assessing early changes in microvascular networks in response to tissue perfusion-altering interventions such as TACE treatment of HCC.

Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain

During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain's macroscopic nerve trajectories. In this study, we investigated the abnormalities of the commissural fibers that connect the left and right cerebral hemispheres in mice lacking heparan sulfate 6-O endosulfatases, Sulf1 and Sulf2 (Sulf1/2), which are extracellular enzymes that remove 6-O sulfate from heparan sulfate and thereby modulate the function of axon guidance factors. We previously demonstrated that Sulf1/2 double knockout (DKO) mouse embryos harbored defects in their corticospinal tract and that some of these DKO mice experienced corpus callosum agenesis. However, abnormalities of the commissural fibers in the adult DKO brain have not been systematically assessed. In this study, we investigated commissural fiber abnormalities in these mice by the combined use of radiological and histological analyses. First, we acquired diffusion-weighted images and three-dimensional-T2 weighted images of adult brains using a 9.4 T animal magnetic resonance imaging system and found that Sulf1/2 DKO mice had a smaller corpus callosum and dorsal hippocampal commissure. Next, we performed myelin staining and anterograde tracing, revealing that the dorsal hippocampal commissure was elongated in a rostral direction. These results suggest that Sulf1/2 play an important role in the formation of commissural tracts and that diffusion tensor imaging associated with microscopic analysis is a powerful tool to clarify nerve tract abnormalities.

Expedient assessment of post-infarct remodeling by native cardiac magnetic resonance imaging in mice

Novel therapeutic strategies aiming at improving the healing process after an acute myocardial infarction are currently under intense investigation. The mouse model plays a central role for deciphering the underlying mechanisms on a molecular and cellular level. Therefore, we intended to assess in-vivo post-infarct remodeling as comprehensively as possible using an expedient native magnetic resonance imaging (MRI) in the two most prominent infarct models, permanent ligation (PL) of the left anterior descending artery (LAD) versus ischemia reperfusion (I/R). Mice were subjected to either permanent or transient (45 min) occlusion of the LAD. After 3 weeks, examinations were performed with a 7-Tesla small animal MRI system. Data analysis was performed with the freely available software Segment. PL resulted in a massive dilation of the left ventricle, accompanied by hypertrophy of the non-infarcted myocardium and a decline of contractile function. These effects were less pronounced following I/R compared to healthy animals. Single plane assessments were not sufficient to capture the specific differences of left ventricular (LV) properties between the two infarct models. Bulls-eye plots were found to be an ideal tool for qualitative LV wall assessment, whereas a multi-slice sector-based analysis of wall regions is ideal to determine differences in hypertrophy, lateral wall thinning and wall thickening on a quantitative level. We combine the use of polar map-based analysis of LV wall properties with volumetric measurements using simple CINE CMR imaging. Our strategy represents a versatile and easily available tool for serial assessment of the LV during the remodeling process. Our study contributes to a better understanding of the effects of novel therapies targeting the healing of damaged myocardium.

A device for the controlled cooling and freezing of excised plant specimens during magnetic resonance imaging

BackgroundInvestigating plant mechanisms to tolerate freezing temperatures is critical to developing crops with superior cold hardiness. However, the lack of imaging methods that allow the visualization of freezing events in complex plant tissues remains a key limitation. Magnetic resonance imaging (MRI) has been successfully used to study many different plant models, including the study of in vivo changes during freezing. However, despite its benefits and past successes, the use of MRI in plant sciences remains low, likely due to limited access, high costs, and associated engineering challenges, such as keeping samples frozen for cold hardiness studies. To address this latter need, a novel device for keeping plant specimens at freezing temperatures during MRI is described.ResultsThe device consists of commercial and custom parts. All custom parts were 3D printed and made available as open source to increase accessibility to research groups who wish to reproduce or iterate on this work. Calibration tests documented that, upon temperature equilibration for a given experimental temperature, conditions between the circulating coolant bath and inside the device seated within the bore of the magnet varied by less than 0.1 °C. The device was tested on plant material by imaging buds from Vaccinium macrocarpon in a small animal MRI system, at four temperatures, 20 °C, − 7 °C, − 14 °C, and − 21 °C. Results were compared to those obtained by independent controlled freezing test (CFT) evaluations. Non-damaging freezing events in inner bud structures were detected from the imaging data collected using this device, phenomena that are undetectable using CFT.ConclusionsThe use of this novel cooling and freezing device in conjunction with MRI facilitated the detection of freezing events in intact plant tissues through the observation of the presence and absence of water in liquid state. The device represents an important addition to plant imaging tools currently available to researchers. Furthermore, its open-source and customizable design ensures that it will be accessible to a wide range of researchers and applications.

Diffusion tensor imaging of brain white matter in rats with ischemia reperfusion injury and its behavioral changes

Objective To investigate the changes of diffusion tensor imaging (DTI) in the cerebral white matter of rats with ischemia-reperfusion injury. Methods Adult SD rats were randomly divided into two groups, sham operation group and model group. The model of ischemia reperfusion injury was made by the Koizumi suture method to occlude the middle cerebral artery. Application of Zea-Longa score was carried out to determine the establishment of modeling, and the modified neurological severity score (mNSS) was used to evaluate the neurological deficit of rats. The Rotarod test instrument was used to observe the motor function of rats by using Rotarod fatigue balance signs, and the DTI sequence scanning observation of brain white matter nerve fiber damage was determined by using Brook 7.0T small animal magnetic resonance imaging system. Track Vis software was used to analyze the distribution of cerebral white matter nerve fibers, and the relative number of nerve fibers in the areas of ROI (region of interest, ROI), sensorimotor areas and striatum were calculated. Results The results showed varying degrees of neurological impairment in rats 2 h after cerebral ischemia reperfusion injury, and the Zea-Longa score and the mNSS score were gradually reduced at the 1 d, 7 d and 14 d after ischemia reperfusion injury. The time of rats retaining on the rotating rod was shortened at the 7 d and 14 d after ischemia reperfusion injury. At the ischemic lateral, nerve fibers decreased significantly, and the number of sensory nerve fiber connections in the sensorimotor areas to striatum was reduced. Nissl staining showed that the cytoplasm of neurons in the sensorimotor cortex and striatum of the ischemic lateral were disappeared and the Nissl bodies were decreased. Conclusions The nerve fibers of sensory motor cortex connecting to striatum were damaged by ischemia reperfusion injury. Key words: Ischemia reperfusion injury; Brain white matter; DTI imaging; Sensorimotor; Striatum

Designing a compact MRI motion phantom

Abstract Even today, dealing with motion artifacts in magnetic resonance imaging (MRI) is a challenging task. Image corruption due to spontaneous body motion complicates diagnosis. In this work, an MRI phantom for rigid motion is presented. It is used to generate motion-corrupted data, which can serve for evaluation of blind motion compensation algorithms. In contrast to commercially available MRI motion phantoms, the presented setup works on small animal MRI systems. Furthermore, retrospective gating is performed on the data, which can be used as a reference for novel motion compensation approaches. The motion of the signal source can be reconstructed using motor trigger signals and be utilized as the ground truth for motion estimation. The proposed setup results in motion corrected images. Moreover, the importance of preprocessing the MRI raw data, e.g. phase-drift correction, is demonstrated. The gained knowledge can be used to design an MRI phantom for elastic motion.

Early Biomarkers in 1H Nuclear Magnetic Resonance Spectroscopy of Striatal Pathological Mechanisms after Acute Carbon Monoxide Poisoning in Rats

ObjectiveIn vivo Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to evaluate the levels of specific neurochemical biomarkers of pathological mechanisms in the brain. MethodsWe conducted T2-Weighted Magnetic Resonance Imaging (MRI) and 1H-MRS with a 3.0-Tesla animal MRI system to investigate the early microstructural and metabolic profiles in vivo in the striatum of rats following carbon monoxide (CO) poisoning. ResultsCompared to baseline, we found significant cortical surface deformation, cerebral edema changes, which were indicated by the unclear gray/white matter border, and lateral ventricular volume changes in the brain. A significant reduction in the metabolite to total creatine (Cr) ratios of N-acetylaspartate (NAA) was observed as early as 1 h after the last CO administration, while the lactate (Lac) levels increased marginally. Both the Lac/Cr and NAA/Cr ratios leveled off at 6 h and showed no subsequent significant changes. In addition, compared to the control, the choline (Cho)/Cr ratio was slightly reduced in the early stages and significantly increased after 6 h. In addition, a pathological examination revealed mild cerebral edema on cessation of the insult and more severe cerebral injury after additional CO poisoning. ConclusionThe present study demonstrated that 1H-MRS of the brain identified early metabolic changes after CO poisoning. Notably, the relationship between the increased Cho/Cr ratio in the striatum and delayed neuropsychologic sequelae requires further research.

Neurobehavioral and imaging correlates of hippocampal atrophy in a mouse model of vascular cognitive impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia. Reduced cerebral blood flow is thought to play a major role in the etiology of VCI. Therefore, chronic cerebral hypoperfusion has been used to model VCI in rodents. The goal of the current study was to determine the histopathological and neuroimaging substrates of neurocognitive impairments in a mouse model of chronic cerebral hypoperfusion induced by unilateral common carotid artery occlusion (UCCAO). Mice were subjected to sham or right UCCAO (VCI) surgeries. Three months later, neurocognitive function was evaluated using the novel object recognition task, Morris water maze, and contextual and cued fear-conditioning tests. Next, cerebral perfusion was evaluated with dynamic susceptibility contrast magnetic resonance imaging (MRI) using an ultra-high field (11.75T) animal MRI system. Finally, brain pathology was evaluated using histology and T2-weighted MRI. VCI, but not sham, mice had significantly reduced cerebral blood flow in the right vs. left cerebral cortex. VCI mice showed deficits in object recognition. T2-weighted MRI of VCI brains revealed enlargement of lateral ventricles, which corresponded to areas of hippocampal atrophy upon histological analysis. In conclusion, our data demonstrate that the UCCAO model of chronic hypoperfusion induces hippocampal atrophy and ventricular enlargement, resulting in neurocognitive deficits characteristic of VCI.

Iterative method for predistortion of MRI gradient waveforms.

The purpose of this work is to correct for transient gradient waveform errors in magnetic resonance imaging (MRI), whether from eddy currents, group delay, or gradient amplifier nonlinearities, which are known to affect image quality. An iterative method is proposed to minimize error between desired and measured gradient waveforms, whose success does not depend on accurate knowledge of the gradient system impulse response. The method was applied to half-pulse excitation for 2-D ultra-short echo time (UTE) imaging on a small animal MRI system and to spiral 2-D excitation on a human 7T MRI system. Predistorted gradient waveforms reduced temporal signal variation caused by excitation gradient trajectory errors in 2-D UTE, and improved the quality of excitation patterns produced by spiral excitation pulses. Iterative gradient predistortion is useful for minimizing transient gradient errors without requiring accurate characterization of the gradient system impulse response.

Small animal magnetic resonance imaging: an efficient tool to assess liver volume and intrahepatic vascular anatomy

BackgroundTo develop a noninvasive technique to assess liver volumetry and intrahepatic portal vein anatomy in a mouse model of liver regeneration. Materials and methodsFifty-two C57BL/6 male mice underwent magnetic resonance imaging (MRI) of the liver using a 4.7 T small animal MRI system after no treatment, 70% partial hepatectomy (PH), or selective portal vein embolization. The protocol consisted of the following sequences: three-dimensional–encoded spoiled gradient-echo sequence (repetition time per echo time 15 per 2.7 ms, flip angle 20°) for volumetry, and two-dimensional–encoded time-of-flight angiography sequence (repetition time per echo time 18 per 6.4 ms, flip angle 80°) for vessel visualization. Liver volume and portal vein segmentation was performed using a dedicated postprocessing software. In animals with portal vein embolization, portography served as reference standard. True liver volume was measured after sacrificing the animals. Measurements were carried out by two independent observers with subsequent analysis by the Cohen κ-test for interobserver agreement. ResultsMRI liver volumetry highly correlated with the true liver volume measurement using a conventional method in both the untreated liver and the liver remnant after 70% PH with a high interobserver correlation coefficient of 0.94 (95% confidence interval, 0.80–0.98 for untreated liver [P < 0.001] and 0.90–0.97 after 70% PH [P < 0.001]). The diagnostic accuracy of magnetic resonance angiography for the occlusion of one branch of the portal vein was 0.95 (95% confidence interval, 0.84–1). The level of agreement between the two observers for the description of intrahepatic vascular anatomy was excellent (Cohen κ value = 0.925). ConclusionsThis protocol may be used for noninvasive liver volumetry and visualization of portal vein anatomy in mice. It will serve the dynamic study of new strategies to enhance liver regeneration in vivo.

Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems

Magnetic resonance imaging (MRI) is widely used in human brain research to evaluate the effects of healthy aging and development, as well as neurological disorders. Although standardized methods for quality assurance of human MRI instruments have been established, such approaches have typically not been translated to small animal imaging. We present a method for the generation and analysis of customized phantoms for small animal MRI systems that allows rapid and accurate system stability monitoring. Computer-aided design software was used to produce a customized phantom using a rapid prototyping printer. Automated registration algorithms were used on three-dimensional images of the phantom to allow system stability to be easily monitored over time. The design of the custom phantom allowed reliable placement relative to the imaging coil. Automated registration showed superior ability to detect gradient changes reflected in the images than with manual measurements. Registering images acquired over time allowed monitoring of gradient drifts of less than one percent. A low cost, MRI compatible phantom was successfully designed using computer-aided design software and a three-dimensional printer. Registering phantom images acquired over time allows monitoring of gradient stability of the MRI system.

Altered brain metabolism after whole body irradiation in mice: A preliminary in vivo 1H MRS study

Purpose: In the classical description of acute radiation syndrome, the role of central nervous system (CNS) is underestimated. It is now well recognised that ionising radiation-induced oxidative stress may bring about functional changes in the brain. In this study, we prospectively evaluated metabolic changes in the brain after whole body irradiation in mice using in vivo proton (1H) nuclear magnetic resonance spectroscopy (MRS).Material and methods: Young adult mice were exposed to whole body irradiation of 8 Gy and controls were sham irradiated. In vivo 1H MRS from cortex-hippocampus and hypothalamic-thalamic region of brain at different time points, i.e., as early as 6 hours, day 1, 2, 3, 5 and 10 post irradiation was carried out at 7 Tesla animal magnetic resonance imaging system. Brain metabolites were measured and quantitative analysis of detectable metabolites was performed by linear combination of model (LCModel).Results: Significant reduction in myoinositol (p = 0.03) and taurine (p = 0.02) ratios were observed in cortex-hippocampus region as early as day 2 post irradiation compared to controls. These metabolic alterations remained sustained over day 10 post irradiation.Conclusions: The results of this preliminary study suggest that the alteration/reduction in the mI and Tau concentration may be associated with physiological perturbations in astrocytes or radiation induced neuro-inflammatory response triggered in microglial cell.

Deformation-based brain morphometry in rats

Magnetic resonance imaging (MRI)-based morphometry provides in vivo evidence for macro-structural plasticity of the brain. Experiments on small animals using automated morphometric methods usually require expensive measurements with ultra-high field dedicated animal MRI systems. Here, we developed a novel deformation-based morphometry (DBM) tool for automated analyses of rat brain images measured on a 3-Tesla clinical whole body scanner with appropriate coils. A landmark-based transformation of our customized reference brain into the coordinates of the widely used rat brain atlas from Paxinos and Watson (Paxinos Atlas) guarantees the comparability of results to other studies. For cross-sectional data, we warped images onto the reference brain using the low-dimensional nonlinear registration implemented in the MATLAB software package SPM8. For the analysis of longitudinal data sets, we chose high-dimensional registrations of all images of one data set to the first baseline image which facilitate the identification of more subtle structural changes. Because all deformations were finally used to transform the data into the space of the Paxinos Atlas, Jacobian determinants could be used to estimate absolute local volumes of predefined regions-of-interest. Pilot experiments were performed to analyze brain structural changes due to aging or photothrombotically-induced cortical stroke. The results support the utility of DBM based on commonly available clinical whole-body scanners for highly sensitive morphometric studies on rats.

P4‐294: MR imaging of arterial dysfunction in a mouse model of Alzheimer's disease

Arterial spin labeling (ASL) magnetic resonance imaging (MRI) has demonstrated regional cerebral hypoperfusion in Alzheimer's disease (AD) patients, as well as murine models of AD. It is well-recognized that cerebral arteries undergo microstructural changes in AD, including deposition of β-amyloid (i.e. cerebral amyloid angiopathy) and loss of smooth muscle cells, resulting in cerebrovascular dysfunction. While compromised arterial function can be assessed in mouse brain by several techniques, these methods are restricted to focal regions of the cortical surface. In order to assess the entire arterial system, we have employed a novel, non-invasive, quantitative approach based on in vivo 3D MRI data. MR image volumes were acquired from 3–5 month-old (young) and 18–20 month-old (aged) APP transgenic (TG) and wild-type (WT) mice. Whole-brain anatomical images and 3D MR arteriograms were acquired on a 7T animal MRI system. The MRI data was processed using a fully-automated pipeline. In order to derive quantitative information from the arteriogram, we utilized a region-of-interest (ROI)-based approach. The ROI labels (vessel segments) were mapped from a standardized atlas in reference space to each mouse brain MRI volume in native space via atlas-based segmentation. We then derived a quantitative measure, the “arterial index”, which is related to the apparent arterial cerebral blood volume (CBV a), for each ROI. Young APP TG mice demonstrated significantly reduced arterial indices relative to WT mice in the distal segments of major cerebral arteries, including middle cerebral, posterior cerebral, and azygos pericallosal arteries (with the exception of the retrosplenial branch), while the proximal segments and the internal carotid were largely unaffected. The pterygopalatine artery demonstrated a higher arterial index in the young TG relative to WT mice. The retrosplenial branch of the azygos pericallosal artery showed greater age-related reduction in the arterial index in TG compared to WT mice. We have demonstrated regional differences in arterial function as a function of genotype (TG vs. WT) and age (young vs. aged). The arterial index may complement conventional ASL perfusion MRI measures, and could potentially serve as a powerful, novel imaging biomarker for the assessment of disease evolution and therapeutic intervention in pre-clinical and clinical studies.

Abstract 2363: Comparison and characterization of two orthotopic glioblastoma in vivo mouse models with human U87 and LN-229 cells using in vivo bioluminescence imaging and magnetic resonance imaging (MRI)

Abstract Glioblastoma is the most common and most aggressive type of malignant brain tumors. The prognosis is poor, with a median survival time of several months only. Despite steady progress in treatment of glioblastomas this tumor entity is still not curable. Thus, there is an urgent need for the development of novel effective therapies, and for appropriate in vivo models to characterize them. Most often novel antiglioblastoma drugs are tested in subcutaneous xenograft mouse models using various human or murine glioblastoma cell lines. To generate more relevant, orthotopic brain cancer in vivo models, we stably transduced the human glioblastoma cell lines U-87 and LN-229 with fire fly luciferase suitable for in vivo bioluminescence imaging. To initiate orthotopic growth, nude mice were anesthetized and placed in a stereotactic fixation device. Through a burr hole cells were implanted intracranially using a Hamilton syringe. Once to twice a week we used bioluminescence imaging to continually monitor tumor growth in vivo. However, as magnetic resonance imaging (MRI) is the most relevant tool to monitor oncological therapy in glioblastomas clinically, we adapted this translational aspect and analysed the mice in parallel using a dedicated animal MRI System. MRI offers detailed information about growth characteristics, size, blood supply and interaction with the surrounding tissue of the tumor. To achieve this, we performed T2-weighted imaging, and diffusion weighted imaging (DWI) weekly to visualise the tumors as well as necrosis and edemas. The use of both methods allowed independent and complementary characterization of the tumors. When exponential growth of the orthotopic tumors was observed, and the tumors reached critical sizes necropsy was done. In vivo bioluminescence imaging revealed only a very dominant signal in the region of the brain where the primary tumor was located. To address potential metastases in more detail we analysed a set of different resected organs and tissues for in vitro luciferase activity followed by extensive histological examination. Currently, we test different anti-glioblastoma agents in these orthotopic models to evaluate an antitumoral effect as well as a potential reduction of the edemas comparing the results in both models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2363. doi:1538-7445.AM2012-2363

Abstract B14: Characterization of an orthotopic glioblastoma in vivo mouse model with firefly luciferase expressing human U87 cells using in vivo bioluminescence imaging and magnetic resonance imaging (MRI).

Abstract Glioblastoma is the most common and most aggressive type of malignant brain tumors. The prognosis is poor, with a median survival time of several months only. Despite steady progress in treatment of glioblastomas this tumor entity is still not curable. Thus, there is an urgent need for the development of novel effective therapies, and for appropriate in vivo models to characterize them. Most often novel antiglioblastoma drugs are tested in subcutaneous xenograft mouse models using various human or murine glioblastoma cell lines. To generate more relevant, orthotopic brain cancer in vivo models, we stably transduced the human glioblastoma cell line U-87 with fire fly luciferase (U-87-Luci) suitable for in vivo bioluminescence imaging. To initiate orthotopic growth, nude mice were anesthetized and placed in a stereotactic fixation device. Through a burr hole cells were implanted intracranially using a Hamilton syringe. Once to twice a week we used bioluminescence imaging to continually monitor tumor growth in vivo. However, as magnetic resonance imaging (MRI) is the most relevant tool to monitor oncological therapy in glioblastomas clinically, we adapted this translational aspect and analysed the mice in parallel using a dedicated animal MRI System. MRI offers detailed information about growth characteristics, size, blood supply and interaction with the surrounding tissue of the tumor. To achieve this, we performed T2-weighted imaging, and diffusion weighted imaging (DWI) weekly to visualise the tumors as well as necrosis and edemas. To monitor the blood supply of the glioblastomas we performed dynamic contrast enhanced MR imaging (DCE-MRI). The use of both methods allowed independent and complementary characterization of the tumors. Approximately four weeks after implantation, exponential growth of the orthotopic tumors was observed, and another two weeks later necropsy was done. In vivo bioluminescence imaging revealed only a very dominant signal in the region of the brain where the primary tumor was located. To address potential metastases in more detail we analysed a set of different resected organs and tissues for in vitro luciferase activity followed by extensive histological examination. Currently, we test different known anti-glioblastoma agents in this orthotopic model to evaluate an antitumoral effect as well as a potential reduction of the edemas. Next, we plan to test carefully novel compounds in order to discover new generations of drugs suitable to help glioblastoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B14.

MRI in rodent models of brain disorders.

Magnetic resonance imaging (MRI) is a well-established tool in clinical practice and research on human neurological disorders. Translational MRI research utilizing rodent models of central nervous system (CNS) diseases is becoming popular with the increased availability of dedicated small animal MRI systems. Projects utilizing this technology typically fall into one of two categories: 1) true "pre-clinical" studies involving the use of MRI as a noninvasive disease monitoring tool which serves as a biomarker for selected aspects of the disease and 2) studies investigating the pathomechanism of known human MRI findings in CNS disease models. Most small animal MRI systems operate at 4.7-11.7 Tesla field strengths. Although the higher field strength clearly results in a higher signal-to-noise ratio, which enables higher resolution acquisition, a variety of artifacts and limitations related to the specific absorption rate represent significant challenges in these experiments. In addition to standard T1-, T2-, and T2*-weighted MRI methods, all of the currently available advanced MRI techniques have been utilized in experimental animals, including diffusion, perfusion, and susceptibility weighted imaging, functional magnetic resonance imaging, chemical shift imaging, heteronuclear imaging, and (1)H or (31)P MR spectroscopy. Selected MRI techniques are also exclusively utilized in experimental research, including manganese-enhanced MRI, and cell-specific/molecular imaging techniques utilizing negative contrast materials. In this review, we describe technical and practical aspects of small animal MRI and provide examples of different MRI techniques in anatomical imaging and tract tracing as well as several models of neurological disorders, including inflammatory, neurodegenerative, vascular, and traumatic brain and spinal cord injury models, and neoplastic diseases.

Gradient-induced longitudinal relaxation of hyperpolarized noble gases in the fringe fields of superconducting magnets used for magnetic resonance

When hyperpolarized noble gases are brought into the bore of a superconducting magnet for magnetic resonance imaging (MRI) or spectroscopy studies, the gases must pass through substantial field gradients, which can cause rapid longitudinal relaxation. In this communication, we present a means of calculating this spatially dependent relaxation rate in the fringe field of typical magnets. We then compare these predictions to experimental measurements of 3He relaxation at various positions near a medium-bore 2-T small animal MRI system. The calculated and measured relaxation rates on the central axis of the magnet agree well and show a maximum 3He relaxation rate of 3.83×10−3s−1 (T1=4.4min) at a distance of 47cm from the magnet isocenter. We also show that if this magnet were self-shielded, its minimum T1 would drop to 1.2min. In contrast, a typical self-shielded 1.5-T clinical MRI scanner will induce a minimum on-axis T1 of 12min. Additionally, we show that the cylindrically symmetric fields of these magnets enable gradient-induced relaxation to be calculated using only knowledge of the on-axis longitudinal field, which can either be measured directly or calculated from a simple field model. Thus, while most MRI magnets employ complex and proprietary current configurations, we show that their fringe fields and the resulting gradient-induced relaxation are well approximated by simple solenoid models. Finally, our modeling also demonstrates that relaxation rates can increase by nearly an order of magnitude at radial distances equivalent to the solenoid radius.