MR relaxation times of agar-based tissue-mimicking phantoms.

Agar gels were previously proven capable of accurately replicating the acoustical and thermal properties of real tissue and widely used for the construction of tissue-mimicking phantoms (TMPs) for focused ultrasound (FUS) applications. Given the current popularity of magnetic resonance-guided FUS (MRgFUS), we have investigated the MR relaxation times T1 and T2 of different mixtures of agar-based phantoms. Nine TMPs were constructed containing agar as the gelling agent and various concentrations of silicon dioxide and evaporated milk. An agar-based phantom doped with wood powder was also evaluated. A series of MR images were acquired in a 1.5 T scanner for T1 and T2 mapping. T2 was predominantly affected by varying agar concentrations. A trend toward decreasing T1 with an increasing concentration of evaporated milk was observed. The addition of silicon dioxide decreased both relaxation times of pure agar gels. The proposed phantoms have great potential for use with the continuously emerging MRgFUS technology. The MR relaxation times of several body tissues can be mimicked by adjusting the concentration of ingredients, thus enabling more accurate and realistic MRgFUS studies.

A functional form for a representative individual arterial input function measured from a population using high temporal resolution DCE MRI.

PURPOSE: To measure the arterial input function (AIF), an essential component of tracer kinetic analysis, in a population of patients using an optimized dynamic contrast-enhanced (DCE) imaging sequence and to estimate inter- and intrapatient variability. From these data, a representative AIF that may be used for realistic simulation studies can be extracted. METHODS: Thirty-nine female patients were imaged on multiple visits before and during a course of neoadjuvant chemotherapy for breast cancer. A total of 97 T1 -weighted DCE studies were analyzed including bookend estimates of T1 and model-fitting to each individual AIF. Area under the curve and cardiac output were estimated from each first pass peak, and these data were used to assess inter- and intrapatient variability of the AIF. RESULTS: Interpatient variability exceeded intrapatient variability of the AIF. There was no change in cardiac output as a function of MR visit (mean value 5.6 ± 1.1 L/min) but baseline blood T1 increased significantly following the start of chemotherapy (which was accompanied by a decrease in hematocrit). CONCLUSION: The AIF in an individual patient can be measured reproducibly but the variability of AIFs between patients suggests that use of a population AIF will decrease the precision of tracer kinetic analysis performed in cross-patient comparison studies. A representative AIF is presented that is typical of the population but retains the characteristics of an individually measured AIF.

Estimating breast tumor blood flow during neoadjuvant chemotherapy using interleaved high temporal and high spatial resolution MRI.

PURPOSE: To evaluate an interleaved MRI sampling strategy that acquires both high temporal resolution (HTR) dynamic contrast-enhanced (DCE) data for quantifying breast tumor blood flow (TBF) and high spatial resolution (HSR) DCE data for clinical reporting, following a single standard injection of contrast agent. METHODS: A simulation study was used to evaluate the performance of the interleaved technique under different conditions. In a prospective clinical study, 18 patients with primary breast cancer, who were due to undergo neoadjuvant chemotherapy (NACT), were examined using interleaved HTR and HSR DCE-MRI at 1.5 Tesla. Tumor regions of interest were analyzed with a two-compartment tracer kinetic model. Paired parameters (n = 10) from the data acquired before and post-cycle 2 of NACT were compared using the nonparametric Wilcoxon signed-rank test. RESULTS: Simulations demonstrated that TBF was reliably estimated using the proposed strategy. The region of interest analysis revealed significant changes in TBF (0.81-0.43 mL/min/mL; P = 0.002) following two cycles of NACT. The HSR data were reported in the normal way and enabled the assessment of tumor volume, which decreased by 53% following NACT (P = 0.065). CONCLUSIONS: TBF can be measured reliably using the proposed strategy without compromising a standard clinical protocol. Furthermore, in our feasibility study, TBF decreased significantly following NACT, whereas capillary permeability surface-area product did not. Magn Reson Med 79:317-326, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

MRI compatibility testing of commercial high intensity focused ultrasound transducers.

PURPOSE: The study aimed to compare the performance of eight commercially available single-element High Intensity Focused Ultrasound (HIFU) transducers in terms of Magnetic Resonance Imaging (MRI) compatibility. METHODS: Imaging of an agar-based MRI phantom was performed in a 3 T MRI scanner utilizing T2-Weighted Fast Spin Echo (FSE) and Fast low angle shot (FLASH) sequences, which are typically employed for high resolution anatomical imaging and thermometry, respectively. Reference magnitude and phase images of the phantom were compared with images acquired in the presence of each transducer in terms of the signal to noise ratio (SNR), introduced artifacts, and overall image quality. RESULTS: The degree of observed artifacts highly differed among the various transducers. The transducer whose backing material included magnetic impurities showed poor performance in the MRI, introducing significant susceptibility artifacts such as geometric distortions and signal void bands. Additionally, it caused the most significant SNR drop. Other transducers were shown to exhibit high level of MRI compatibility as the resulting images closely resembled the reference images with minimal to no apparent artifacts and comparable SNR values. CONCLUSIONS: The study findings may facilitate researchers to select the most suitable transducer for their research, simultaneously avoiding unnecessary testing. The study further provides useful design considerations for MRI compatible transducers.

Tumor phantom model for MRI-guided focused ultrasound ablation studies.

BACKGROUND: The persistent development of focused ultrasound (FUS) thermal therapy in the context of oncology creates the need for tissue-mimicking tumor phantom models for early-stage experimentation and evaluation of relevant systems and protocols. PURPOSE: This study presents the development and evaluation of a tumor-bearing tissue phantom model for testing magnetic resonance imaging (MRI)-guided FUS (MRgFUS) ablation protocols and equipment based on MR thermometry. METHODS: Normal tissue was mimicked by a pure agar gel, while the tumor simulator was differentiated from the surrounding material by including silicon dioxide. The phantom was characterized in terms of acoustic, thermal, and MRI properties. US, MRI, and computed tomography (CT) images of the phantom were acquired to assess the contrast between the two compartments. The phantom's response to thermal heating was investigated by performing high power sonications with a 2.4 MHz single element spherically focused ultrasonic transducer in a 3T MRI scanner. RESULTS: The estimated phantom properties fall within the range of literature-reported values of soft tissues. The inclusion of silicon dioxide in the tumor material offered excellent tumor visualization in US, MRI, and CT. MR thermometry revealed temperature elevations in the phantom to ablation levels and clear evidence of larger heat accumulation within the tumor owing to the inclusion of silicon dioxide. CONCLUSION: Overall, the study findings suggest that the proposed tumor phantom model constitutes a simple and inexpensive tool for preclinical MRgFUS ablation studies, and potentially other image-guided thermal ablation applications upon minimal modifications.

Ca+ activity maps of astrocytes tagged by axoastrocytic AAV transfer.

Astrocytes exhibit localized Ca2+ microdomain (MD) activity thought to be actively involved in information processing in the brain. However, functional organization of Ca2+ MDs in space and time in relationship to behavior and neuronal activity is poorly understood. Here, we first show that adeno-associated virus (AAV) particles transfer anterogradely from axons to astrocytes. Then, we use this axoastrocytic AAV transfer to express genetically encoded Ca2+ indicators at high-contrast circuit specifically. In combination with two-photon microscopy and unbiased, event-based analysis, we investigated cortical astrocytes embedded in the vibrissal thalamocortical circuit. We found a wide range of Ca2+ MD signals, some of which were ultrafast (≤300 ms). Frequency and size of signals were extensively increased by locomotion but only subtly with sensory stimulation. The overlay of these signals resulted in behavior-dependent maps with characteristic Ca2+ activity hotspots, maybe representing memory engrams. These functional subdomains are stable over days, suggesting subcellular specialization.

Challenges regarding MR compatibility of an MRgFUS robotic system.

Numerous challenges are faced when employing Magnetic Resonance guided Focused Ultrasound (MRgFUS) hardware in the Magnetic Resonance Imaging (MRI) setting. The current study aimed to provide insights on this topic through a series of experiments performed in the framework of evaluating the MRI compatibility of an MRgFUS robotic device. All experiments were performed in a 1.5 T MRI scanner. The main metric for MRI compatibility assessment was the signal to noise ratio (SNR). Measurements were carried out in a tissue mimicking phantom and freshly excised pork tissue under various activation states of the system. In the effort to minimize magnetic interference and image distortion, various set-up parameters were examined. Significant SNR degradation and image distortion occurred when the FUS transducer was activated mainly owing to FUS-induced target and coil vibrations and was getting worse as the output power was increased. Proper design and stable positioning of the imaged phantom play a critical role in reducing these vibrations. Moreover, isolation of the phantom from the imaging coil was proven essential for avoiding FUS-induced vibrations from being transferred to the coil during sonication and resulted in a more than 3-fold increase in SNR. The use of a multi-channel coil increased the SNR by up to 50 % compared to a single-channel coil. Placement of the electronics outside the coil detection area increased the SNR by about 65 %. A similar SNR improvement was observed when the encoders' counting pulses were deactivated. Overall, this study raises awareness about major challenges regarding operation of an MRgFUS system in the MRI environment and proposes simple measures that could mitigate the impact of noise sources so that the monitoring value of MR imaging in FUS applications is not compromised.

Simple methods to test the accuracy of MRgFUS robotic systems.

BACKGROUND: Robotic-assisted diagnostic and therapeutic modalities require a highly accurate performance to be certified for clinical application. In this paper, three simple methods for assessing the accuracy of motion of magnetic resonance-guided focused ultrasound (MRgFUS) robotic systems are presented. METHODS: The accuracy of motion of a 4 degrees of freedom robotic system intended for preclinical use of MRgFUS was evaluated by calliper-based and magnetic resonance imaging (MRI) methods, as well as visually by performing multiple ablations on a plastic film. RESULTS: The benchtop results confirmed a highly accurate motion in all axes of operation. The spatial positioning errors estimated by MRI evaluation were defined by the size of the imaging pixels. Lesions arrangement in discrete and overlapping patterns confirmed satisfactory alignment of motion trajectories. CONCLUSIONS: We believe the methods presented here should serve as a standard for evaluating the accuracy of motion of MRgFUS robotic systems.

Breast tumour volume and blood flow measured by MRI after one cycle of epirubicin and cyclophosphamide-based neoadjuvant chemotherapy as predictors of pathological response.

OBJECTIVES: Better markers of early response to neoadjuvant chemotherapy (NACT) in patients with breast cancer are required to enable the timely identification of non-responders and reduce unnecessary treatment side-effects. Early functional imaging may better predict response to treatment than conventional measures of tumour size. The purpose of this study was to test the hypothesis that the change in tumour blood flow after one cycle of NACT would predict pathological response. METHODS: In this prospective cohort study, dynamic contrast-enhanced MRI was performed in 35 females with breast cancer before and after one cycle of epirubicin and cyclophosphamide-based NACT (EC90). Estimates of tumour blood flow and tumour volume were compared with pathological response obtained at surgery following completion of NACT. RESULTS: Tumour blood flow at baseline (mean ± SD; 0.32 ± 0.17 ml/min/ml) reduced slightly after one cycle of NACT (0.28 ± 0.18 ml/min/ml). Following treatment 15 patients were identified as pathological responders and 20 as non-responders. There were no relationships found between tumour blood flow and pathological response. Conversely, tumour volume was found to be a good predictor of pathological response (smaller tumours did better) at both baseline (area under the receiver operating characteristic curve 0.80) and after one cycle of NACT (area under the receiver operating characteristic curve 0.81). CONCLUSION & ADVANCES IN KNOWLEDGE: The change in breast tumour blood flow following one cycle of EC90 did not predict pathological response. Tumour volume may be a better early marker of response with such agents.

Modeling Gadoxetate Liver Uptake and Efflux Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging Enables Preclinical Quantification of Transporter Drug-Drug Interactions.

OBJECTIVES: The aim of this study was to model the in vivo transporter-mediated uptake and efflux of the hepatobiliary contrast agent gadoxetate in the liver. The efficacy of the proposed technique was assessed for its ability to provide quantitative insights into drug-drug interactions (DDIs), using rifampicin as inhibitor. MATERIALS AND METHODS: Three groups of C57 mice were scanned twice with a dynamic gadoxetate-enhanced magnetic resonance imaging protocol, using a 3-dimensional spoiled gradient-echo sequence for approximately 72 minutes. Before the second magnetic resonance imaging session, 2 of the groups received a rifampicin dose of 20 (n = 7) or 40 (n = 7) mg/kg, respectively. Data from regions of interest in the liver were analyzed using 2 simplifications of a 2-compartment uptake and efflux model to provide estimates for the gadoxetate uptake rate (ki) into the hepatocytes and its efflux rate (kef) into the bile. Both models were assessed for goodness-of-fit in the group without rifampicin (n = 9), and the appropriate model was selected for assessing the ability to monitor DDIs in vivo. RESULTS: Seven of 9 mice from the group without rifampicin were assessed for model implementation and reproducibility. A simple 3 parameter model (ki, kef, and extracellular space, vecs) adequately described the observed liver concentration time series with mean ki = 0.47 ± 0.11 min and mean kef = 0.039 ± 0.016 min. Visually, the area under the liver concentration time profile was reduced for the groups receiving rifampicin. Furthermore, tracer kinetic modeling demonstrated a significant dose-dependent decrease in the uptake (5.9- and 17.3-fold decrease for 20 mg/kg and 40 mg/kg, respectively) and efflux rates (2.2- and 7.9-fold decrease) compared with the first scan for each group. CONCLUSIONS: This study presents the first in vivo implementation of a 2-compartment uptake and efflux model to monitor DDIs at the transporter-protein level, using the clinically relevant organic anion transporting polypeptide inhibitor rifampicin. The technique has the potential to be a novel alternative to other methods, allowing real-time changes in transporter DDIs to be measured directly in vivo.

Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging: Monitoring Transporter-Mediated Processes in Healthy Volunteers.

OBJECTIVE: The objective of this study was to use noninvasive dynamic contrast-enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers. MATERIALS AND METHODS: Ten healthy volunteers (age range, 18-29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast-enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time. RESULTS: Eight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 ± 0.05 and 0.017 ± 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 ± 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: ±0.02/min, kef: ±0.004/min) was lower compared with the individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes. CONCLUSIONS: This is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions.