Fast quantitative MRI: Spiral Acquisition Matching-Based Algorithm (SAMBA) for Robust T1 and T2 Mapping.

Conventional diagnostic images from Magnetic Resonance Imaging (MRI) are typically qualitative and require subjective interpretation. Alternatively, quantitative MRI (qMRI) methods have become more prevalent in recent years with multiple clinical and preclinical imaging applications. Quantitative MRI studies on preclinical MRI scanners are being used to objectively assess tissues and pathologies in animal models and to evaluate new molecular MRI contrast agents. Low-field preclinical MRI scanners (≤3.0T) are particularly important in terms of evaluating these new MRI contrast agents at human MRI field strengths. Unfortunately, these low-field preclinical qMRI methods are challenged by long acquisition times, intrinsically low MRI signal levels, and susceptibility to motion artifacts. In this study, we present a new rapid qMRI method for a preclinical 3.0T MRI scanner that combines a Spiral Acquisition with a Matching-Based Algorithm (SAMBA) to rapidly and quantitatively evaluate MRI contrast agents. In this initial development, we compared SAMBA with gold-standard Spin Echo MRI methods using Least Squares Fitting (SELSF) in vitro phantoms and demonstrated shorter scan times without compromising measurement accuracy or repeatability. These initial results will pave the way for future in vivo qMRI studies using state-of-the-art chemical probes.

RF coil that minimizes electronic components while enhancing performance for rodent MRI at 7 Tesla.

This study introduces a novel volume coil design that features two slotted end-plates connected by six rungs, resembling the traditional birdcage coil. The end rings are equipped with six evenly distributed circular slots, inspired by Mansfield's cavity resonator theory, which suggests that circular slots can generate a baseline resonant frequency. One notable advantage of this proposed coil design is its reduced reliance on electronic components compared to other volume coils, making it more efficient. Additionally, the dimensions of the coil can be theoretically computed in advance, enhancing its practicality. To evaluate the performance and safety of the coil, electromagnetic field and specific absorption rate simulations were simulated using a cylindrical saline phantom and the finite element method. Furthermore, a transceiver coil prototype optimized for 7 Tesla and driven in quadrature was constructed, enabling whole-body imaging of rats. The resonant frequency of the coil prototype obtained through experimental measurements closely matched the theoretical frequency derived from Mansfield's theory. To validate the coil design, phantom images were acquired to demonstrate its viability and assess its performance. These images also served to validate the magnetic field simulations. The experimental results aligned well with the simulation findings, confirming the reliability of the proposed coil design. Importantly, the prototype coil showcased significant improvements over a similarly-sized birdcage coil, indicating its potential for enhanced performance. The noise figure was lower in the prototype versus the birdcage coil (NFbirdcage-NFslotcage= 0.7). Phantom image data were also used to compute the image SNR, giving SNRslotcage/SNRbirdcage= 34.36/24.34. By proving the feasibility of the coil design through successful rat whole-body imaging, the study provides evidence supporting its potential as a viable option for high-field MRI applications on rodents.

Ablation of oligodendrogenesis in adult mice alters brain microstructure and activity independently of behavioral deficits.

Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice leads to learning and memory deficits in a range of behavioral tasks. The current study replicated and re-evaluated evidence for a role of oligodendrogenesis in motor learning, using a complex running wheel task. Further, we found that ablating oligodendrogenesis alters brain microstructure (ex vivo MRI) and brain activity (in vivo EEG) independent of experience with the task. This suggests a role for adult oligodendrocyte formation in the maintenance of brain function and indicates that task-independent changes due to oligodendrogenesis ablation need to be considered when interpreting learning and memory deficits in this model.

Preclinical magnetic resonance imaging and spectroscopy in the fields of radiological technology, medical physics, and radiology.

Magnetic resonance imaging (MRI) is an indispensable diagnostic imaging technique used in the clinical setting. MRI is advantageous over X-ray and computed tomography (CT), because the contrast provided depends on differences in the density of various organ tissues. In addition to MRI systems in hospitals, more than 100 systems are used for research purposes in Japan in various fields, including basic scientific research, molecular and clinical investigations, and life science research, such as drug discovery, veterinary medicine, and food testing. For many years, additional preclinical imaging studies have been conducted in basic research in the fields of radiation technology, medical physics, and radiology. The preclinical MRI research includes studies using small-bore and whole-body MRI systems. In this review, we focus on the animal study using small-bore MRI systems as "preclinical MRI". The preclinical MRI can be used to elucidate the pathophysiology of diseases and for translational research. This review will provide an overview of previous preclinical MRI studies such as brain, heart, and liver disease assessments. Also, we provide an overview of the utility of preclinical MRI studies in radiological physics and technology.

Autonomous animal heating and cooling system for temperature-regulated magnetic resonance experiments.

Temperature is a hallmark parameter influencing almost all magnetic resonance properties (e.g., T1 , T2 , proton density, and diffusion). In the preclinical setting, temperature has a large influence on animal physiology (e.g., respiration rate, heart rate, metabolism, and oxidative stress) and needs to be carefully regulated, especially when the animal is under anesthesia and thermoregulation is disrupted. We present an open-source heating and cooling system capable of regulating the temperature of the animal. The system was designed using Peltier modules capable of heating or cooling a circulating water bath with active temperature feedback. Feedback was obtained using a commercial thermistor, placed in the animal rectum, and a proportional-integral-derivative controller was used to modulate the temperature. Its operation was demonstrated in a phantom as well as in mouse and rat animal models, where the standard deviation of the temperature of the animal upon convergence was less than a 10th of a degree. An application where brain temperature of a mouse was modulated was demonstrated using an invasive optical probe and noninvasive magnetic resonance spectroscopic thermometry measurements.

Evaluation of Apparent Diffusion Coefficient Repeatability and Reproducibility for Preclinical MRIs Using Standardized Procedures and a Diffusion-Weighted Imaging Phantom.

Relevant to co-clinical trials, the goal of this work was to assess repeatability, reproducibility, and bias of the apparent diffusion coefficient (ADC) for preclinical MRIs using standardized procedures for comparison to performance of clinical MRIs. A temperature-controlled phantom provided an absolute reference standard to measure spatial uniformity of these performance metrics. Seven institutions participated in the study, wherein diffusion-weighted imaging (DWI) data were acquired over multiple days on 10 preclinical scanners, from 3 vendors, at 6 field strengths. Centralized versus site-based analysis was compared to illustrate incremental variance due to processing workflow. At magnet isocenter, short-term (intra-exam) and long-term (multiday) repeatability were excellent at within-system coefficient of variance, wCV [±CI] = 0.73% [0.54%, 1.12%] and 1.26% [0.94%, 1.89%], respectively. The cross-system reproducibility coefficient, RDC [±CI] = 0.188 [0.129, 0.343] µm2/ms, corresponded to 17% [12%, 31%] relative to the reference standard. Absolute bias at isocenter was low (within 4%) for 8 of 10 systems, whereas two high-bias (>10%) scanners were primary contributors to the relatively high RDC. Significant additional variance (>2%) due to site-specific analysis was observed for 2 of 10 systems. Base-level technical bias, repeatability, reproducibility, and spatial uniformity patterns were consistent with human MRIs (scaled for bore size). Well-calibrated preclinical MRI systems are capable of highly repeatable and reproducible ADC measurements.

Impact of Cerebral Amyloid Angiopathy in Two Transgenic Mouse Models of Cerebral ß-Amyloidosis: A Neuropathological Study.

The pathological accumulation of parenchymal and vascular amyloid-beta (Aß) are the main hallmarks of Alzheimer's disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively. Emerging evidence raises an important contribution of vascular dysfunction in AD pathology that could partially explain the failure of anti-Aß therapies in this field. Transgenic mice models of cerebral ß-amyloidosis are essential to a better understanding of the mechanisms underlying amyloid accumulation in the cerebrovasculature and its interactions with neuritic plaque deposition. Here, our main objective was to evaluate the progression of both parenchymal and vascular deposition in APP23 and 5xFAD transgenic mice in relation to age and sex. We first showed a significant age-dependent accumulation of extracellular Aß deposits in both transgenic models, with a greater increase in APP23 females. We confirmed that CAA pathology was more prominent in the APP23 mice, demonstrating a higher progression of Aß-positive vessels with age, but not linked to sex, and detecting a pronounced burden of cerebral microbleeds (cMBs) by magnetic resonance imaging (MRI). In contrast, 5xFAD mice did not present CAA, as shown by the negligible Aß presence in cerebral vessels and the occurrence of occasional cMBs comparable to WT mice. In conclusion, the APP23 mouse model is an interesting tool to study the overlap between vascular and parenchymal Aß deposition and to evaluate future disease-modifying therapy before its translation to the clinic.

Analysis of accelerated 4D flow MRI in the murine aorta by radial acquisition and compressed sensing reconstruction.

Preclinical 4D flow MRI remains challenging and is restricted for parallel imaging acceleration due to the limited number of available receive channels. A radial acquisition with combined parallel imaging and temporal compressed sensing reconstruction was implemented to achieve accelerated preclinical 4D flow MRI. In order to increase the accuracy of the measured velocities, a quantitative evaluation of different temporal regularization weights for the compressed sensing reconstruction based on velocity instead of magnitude data is performed. A 3D radial retrospectively triggered phase contrast sequence with a combined parallel imaging and compressed sensing reconstruction with temporal regularization was developed. It was validated in a phantom and in vivo (C57BL/6 J mice), against an established fully sampled Cartesian sequence. Different undersampling factors (USFs [12, 15, 20, 30, 60]) were evaluated, and the effect of undersampling was analyzed in detail for magnitude and velocity data. Temporal regularization weights λ were evaluated for different USFs. Acceleration factors of up to 20 compared with full Nyquist sampling were achieved. The peak flow differences compared with the Cartesian measurement were the following: USF 12, 3.38%; USF 15, 4.68%; USF 20, 0.95%. The combination of 3D radial center-out trajectories and compressed sensing reconstruction is robust against motion and flow artifacts and can significantly reduce measurement time to 30 min at a resolution of 180 µm3 . Concisely, radial acquisition with combined compressed sensing and parallel imaging proved to be an excellent method for analyzing complex flow patterns in mice.

Toward precise arterial input functions derived from DCE-MRI through a novel extracorporeal circulation approach in mice.

PURPOSE: Dynamic contrast-enhanced MRI can be used in pharmacokinetic models to quantify functional parameters such as perfusion and permeability. However, precise quantification in preclinical models is challenged by the difficulties to dynamically measure the true arterial blood contrast agent concentration. We propose a novel approach toward a precise and experimentally feasible method to derive the arterial input function from DCE-MRI in mice. METHODS: Arterial blood was surgically shunted from the femoral artery to the tail vein and led through an extracorporeal circulation that resided on the head of brain tumor-bearing mice inside the FOV of a 9.4T MRI scanner. Dynamic 3D-FLASH scanning was performed after injection of gadobutrol with an effective resolution of 0.175 × 0.175 × 1 mm and a temporal resolution of 4 seconds. Pharmacokinetic modeling was performed using the extended Tofts and two-compartment exchange model. RESULTS: Arterial input functions measured inside the extracorporeal circulation showed little noise, small interindividual variance, and typical curve shapes. Ex vivo and mass spectrometry validation measurements documented the influence of shunt flow velocity and hematocrit on estimation of contrast agent concentrations. Modeling of tumors and muscles allowed fitting of the recorded dynamic concentrations, resulting in quantitative plausible parameters. CONCLUSION: The extracorporeal circulation allows deriving the contrast agent dynamics in arterial blood with high robustness and at acceptable experimental effort from DCE-MRI, previously not achievable in mice. It sets the basis for quantitative precise pharmacokinetic modeling in small animals to enhance the translatability of preclinical DCE-MRI measurements to patients.

Diffusion Kurtosis Imaging as a Tool in Neurotoxicology.

This commentary serves as an introduction to the magnetic resonance imaging (MRI) technique called diffusion kurtosis imaging (DKI) employed in the study by Arab et al. in the present issue of Neurotoxicology Research. In their study, DKI is employed for longitudinal investigation of a methamphetamine intoxication model of Parkinson's disease. The study employs an impressive number of animals and combines DKI with behavioral analysis at multiple time points. The commentary discusses some aspects of the study design especially the strength of combining behavioral analysis with MRI in an effort to provide as thorough a characterization and validity assessment of the animal model and cohort as possible. The potential clinical value of combining multiple MRI techniques (multimodal MRI) in PD is discussed as well as the benefit of multimodal MRI combined with behavioral analysis and subsequent histological analysis for in-depth characterization of animal models.

Subarachnoid hemorrhage in rats - Visualizing blood distribution in vivo using gadolinium-enhanced magnetic resonance imaging: Technical note.

BACKGROUND: The aims of this study were to assess the feasibility of magnetic resonance imaging (MRI) to track the in vivo distribution of autologous, injected blood in a subarachnoid hemorrhage model (SAH), and to evaluate whether this technique results in observable morphological detriment. NEW METHOD: We used an SAH model of stereotactic injection of autologous blood into the prechiasmatic cistern in Sprague Dawley rats. To visualize its in vivo distribution, a gadolinium-containing contrast agent was added to the autologous blood prior to injection. MRI was performed on a 9.4 T Bruker Biospec scanner preoperatively, as well as at variable time points between 30 min to 23 days after SAH. T1-weighted and diffusion-weighted images were acquired. The morphological examination was completed by a histopathological work-up. RESULTS: Upon injection of contrast agent-enriched autologous blood, enhancement was observed in the entire subarachnoid space within 30 min of injection. Total clearance was noted at the first postoperative day. SAH induction did not result in changes in clinical scores or on histopathological or radiological images. COMPARISON WITH EXISTING METHODS: We modified an established method to allow in vivo MRI monitoring of subarachnoid blood distribution in an SAH model. CONCLUSION: This technique could be used to evaluate the distribution of blood components during the development of novel SAH models. Since no additional morphological detriment was observed, this technique could be used as a validation tool to verify correct application and induction in preclinical SAH models.

Longitudinal preclinical magnetic resonance imaging of diffuse tumor burden in intramedullary myeloma following bortezomib therapy.

Multiple myeloma (MM) is a largely incurable, debilitating hematologic malignancy of terminally differentiated plasma cells in the bone marrow (BM). Identification of therapeutic response is critical for improving outcomes and minimizing costs and off-target toxicities. To assess changes in BM environmental factors and therapy efficacy, there is a need for noninvasive, nonionizing, longitudinal, preclinical methods. Here, we demonstrate the feasibility of preclinical magnetic resonance imaging (MRI) for longitudinal imaging of diffuse tumor burden in a syngeneic, immunocompetent model of intramedullary MM. C57Bl/KaLwRij mice were implanted intravenously with 5TGM1-GFP tumors and treated with a proteasome inhibitor, bortezomib, or vehicle control. MRI was performed weekly with a Helmholtz radiofrequency coil placed on the hind leg. Mean normalized T1-weighted signal intensities and T2 relaxation times were quantified for each animal following manual delineation of BM regions in the femur and tibia. Finally, tumor burden was quantified for each tissue using hematoxylin and eosin staining. Changes in T2 relaxation times correlated strongly to cell density and overall tumor burden in the BM. Median T2 relaxation times and regional T1-weighted contrast uptake were shown to be most relevant in identifying posttherapy disease stage in this model of intramedullary MM. In summary, our results highlighted potential preclinical MRI markers for assessing tumor burden and BM heterogeneity following bortezomib therapy, and demonstrated the application of longitudinal imaging with preclinical MRI in an immunocompetent, intramedullary setting.

Oxycodone Exposure: A Magnetic Resonance Imaging Study in Response to Acute and Chronic Oxycodone Treatment in Rats.

The present study was designed to use blood-oxygen-level dependent (BOLD) imaging to "fingerprint" the change in activity in response to oxycodone (OXY) in drug naïve rats before and after repeated exposure to OXY. It was hypothesized that repeated exposure to OXY would initiate adaptive changes in brain organization that would be reflected in an altered response to opioid exposure. Male rats exposed to OXY repeatedly showed conditioned place preference, evidence of drug-seeking behavior and putative neuroadaptation. As these studies were done on awake rats we discovered it was not possible to image rats continuously exposed to OXY due to motion artifact judged to be withdrawal while in the scanner. To circumvent this problem manganese-enhanced MRI (MEMRI) was used to map the distributed integrated activity pattern resulting from continuous OXY exposure. Rats were administered OXY (2.5 mg/kg, i.p.) during image acquisition and changes in BOLD signal intensity were recorded and the activation and deactivation of integrated neural circuits involved in olfaction and motivation were identified. Interestingly, the circuitry of the mesencephalic dopaminergic system showed little activity to the first exposure of OXY. In the MEMRI study, rats received OXY treatments (2.5 mg/kg, twice daily) for four consecutive days following intraventricular MnCl2. Under isoflurane anesthesia, T1-weighted images were acquired and subsequently analyzed showing activity in the forebrain limbic system, ventral striatum, accumbens, amygdala and hippocampus. These results show brain activity is markedly different when OXY is presented to drug naïve rats versus rats with prior, repeated exposure to drug.

Optimization of molecularly targeted MRI in the brain: empirical comparison of sequences and particles.

BACKGROUND: Molecular MRI is an evolving field of research with strong translational potential. Selection of the appropriate MRI sequence, field strength and contrast agent depend largely on the application. The primary aims of the current study were to: 1) assess the sensitivity of different MRI sequences for detection of iron oxide particles in mouse brain; 2) determine the effect of magnetic field strength on detection of iron oxide particles in vivo; and 3) compare the sensitivity of targeted microparticles of iron oxide (MPIO) or ultra-small superparamagnetic iron oxide (USPIO) for detection of vascular cell adhesion molecule-1 (VCAM-1) in vivo. METHODS: Mice were injected intrastriatally with interleukin 1ß to induce VCAM-1 expression on the cerebral vasculature. Subsequently, animals were injected intravenously with either VCAM-MPIO or VCAM-USPIO and imaged 1 or 13 hours post-injection, respectively. MRI was performed at 4.7, 7.0, or 9.4 T, using three different T2*-weighted sequences: single gradient echo 3D (GE3D), multi-gradient echo 3D (MGE3D) and balanced steady-state free precession 3D (bSSFP3D). RESULTS: MGE3D yielded the highest signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) for the detection of iron oxide particles. All sequences showed a significant increase in SNR and CNR from 4.7 to 7.0 T, but no further improvement at 9.4 T. However, whilst targeted MPIO enabled sensitive detection of VCAM-1 expression on the cerebral vasculature, the long half-life (16.5 h vs 1.2 min) and lower relaxivity per particle (1.29×10-14 vs 1.18×10-9 Hz L/particle) of USPIO vs. MPIO rendered them impractical for molecular MRI. CONCLUSION: These findings demonstrate clear advantages of MPIO compared to USPIO for molecularly-targeted MRI, and indicate that the MGE3D sequence is optimal for MPIO detection. Moreover, higher field strengths (7.0/9.4 T) showed enhanced sensitivity over lower field strengths (4.7 T). With the development of biodegradable MPIO, these agents hold promise for clinical translation.

Recent advances in preclinical and clinical multimodal MR in the newborn brain.

Aside from injury identification, MRI of the newborn brain has given us insight into cortical and white matter development, identified windows of vulnerabilities, enabled the introduction of therapeutic hypothermia which has become the standard of care in neonatal asphyxia, and is fostering leapfrogging discoveries in the field of neuro-genetics. This article reviews the main advances in recent years in newborn brain imaging both in preclinical and clinical research.

Dynamic Susceptibility Contrast MRI in Small Animals.

The use of magnetic resonance imaging (MRI) for studying the cerebral perfusion mechanisms is well proved and contrasted in the clinical and research setups. This methodology is a promising tool in assessing numerous brain diseases like intracranial tumors, neurodegeneration processes, mental disorders, injuries and so on. In the preclinical environment, perfusion MRI offers a powerful resource for characterizing pathological models and specially identifying biomarkers to monitor the illness and validate the efficacy of therapeutical approaches. This chapter presents the theoretical bases and experimental protocols of dynamic susceptibility contrast MRI acquisitions for developing perfusion MRI studies in small animals.

Diffusion-Weighted Magnetic Resonance Imaging.

Magnetic resonance imaging (MRI) is a technique based on the contents and relaxation features of water in tissues. In basic MRI sequences, diffusion phenomenon of water molecules is not taken into account although it has a notable influence in the relaxation times, and therefore in the signal intensity of images. In fact, MRI techniques that take advantage of water diffusion have experienced a huge development in last years. Diffusion-weighted imaging (DWI) has spectacularly evolved reaching nowadays a great impact both in clinical and preclinical imaging-especially in the neuroimaging field-and in basic research. We present here a protocol to perform DWI studies in a high-field preclinical setup.

Mapping Functional Connectivity in the Rodent Brain Using Electric-Stimulation fMRI.

Since its discovery in the early 90s, BOLD signal-based functional Magnetic Resonance Imaging (fMRI) has become a fundamental technique for the study of brain activity in basic and clinical research. Functional MRI signals provide an indirect but robust and quantitative readout of brain activity through the tight coupling between cerebral blood flow and neuronal activation, the so-called neurovascular coupling. Combined with experimental techniques only available in animal models, such as intracerebral micro-stimulation, optogenetics or pharmacogenetics, provides a powerful framework to investigate the impact of specific circuit manipulations on overall brain dynamics. The purpose of this chapter is to provide a comprehensive protocol to measure brain activity using fMRI with intracerebral electric micro-stimulation in murine models. Preclinical research (especially in rodents) opens the door to very sophisticated and informative experiments, but at the same time imposes important constrains (i.e., anesthetics, translatability), some of which will be addressed here.

9.4 T small animal MRI using clinical components for direct translational studies.

BACKGROUND: Magnetic resonance is a major preclinical and clinical imaging modality ideally suited for longitudinal studies, e.g. in pharmacological developments. The lack of a proven platform that maintains an identical imaging protocol between preclinical and clinical platforms is solved with the construction of an animal scanner based on clinical hard- and software. METHODS: A small animal magnet and gradient system were connected to a clinical MR system. Several hardware components were either modified or built in-house to achieve compatibility. The clinical software was modified to account for the different field-of-view of a preclinical MR system. The established scanner was evaluated using clinical QA protocols, and platform compatibility for translational research was verified against clinical scanners of different field strength. RESULTS: The constructed animal scanner operates with the majority of clinical imaging sequences. Translational research is greatly facilitated as protocols can be shared between preclinical and clinical platforms. Hence, when maintaining sequences parameters, maximum similarity between pulses played out on a human or an animal system is maintained. CONCLUSION: Coupling of a small animal magnet with a clinical MR system is a flexible, easy to use way to establish and advance translational imaging capability. It provides cost and labor efficient translational capability as no tedious sequence reprogramming between moieties is required and cross-platform compatibility of sequences facilitates multi-center studies.

Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline.

Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline.