Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Development of an MR-Guided Focused Ultrasound (MRgFUS) Lesioning Approach for the Fornix in the Rat Brain.

OBJECTIVE: High-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive therapy to lesion brain tissue, used clinically in patients and pre-clinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of ∼0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. METHODS: The study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n = 7 lesions) was compared to a craniectomy approach (n = 22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using histologic methods from a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. RESULTS: Comparing a motorized adjustment system (∼1 mm precision, n = 17 lesions) to the motorized system with an added micromanipulator (∼0.1 mm precision, n = 14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. CONCLUSIONS: The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models.

Evaluation of acoustic-thermal simulations of in vivo magnetic resonance guided focused ultrasound ablative therapy.

PURPOSE: To evaluate numerical simulations of focused ultrasound (FUS) with a rabbit model, comparing simulated heating characteristics with magnetic resonance temperature imaging (MRTI) data collected during in vivo treatment. METHODS: A rabbit model was treated with FUS sonications in the biceps femoris with 3D MRTI collected. Acoustic and thermal properties of the rabbit muscle were determined experimentally. Numerical models of the rabbits were created, and tissue-type-specific properties were assigned. FUS simulations were performed using both the hybrid angular spectrum (HAS) method and k-Wave. Simulated power deposition patterns were converted to temperature maps using a Pennes' bioheat equation-based thermal solver. Agreement of pressure between the simulation techniques and temperature between the simulation and experimental heating was evaluated. Contributions of scattering and absorption attenuation were considered. RESULTS: Simulated peak pressures derived using the HAS method exceeded the simulated peak pressures from k-Wave by 1.6 ± 2.7%. The location and FWHM of the peak pressure calculated from HAS and k-Wave showed good agreement. When muscle acoustic absorption value in the simulations was adjusted to approximately 54% of the measured attenuation, the average root-mean-squared error between simulated and experimental spatial-average temperature profiles was 0.046 ± 0.019 °C/W. Mean distance between simulated and experimental COTMs was 3.25 ± 1.37 mm. Transverse FWHMs of simulated sonications were smaller than in in vivo sonications. Longitudinal FWHMs were similar. CONCLUSIONS: Presented results demonstrate agreement between HAS and k-Wave simulations and that FUS simulations can accurately predict focal position and heating for in vivo applications in soft tissue.

MR-Guided Focused Ultrasound Thalamotomy in the Setting of Aneurysm Clip.

We report on a 75-year-old woman with a history of right MCA aneurysm clipping and medically refractive right-hand tremor. We successfully performed focused ultrasound thalamotomy of the left ventral intermediate nucleus under MR imaging-guidance at 3T. A thorough pretreatment evaluation of MR thermometry was critical to ensure that adequate precision could be achieved at the intended target. The tremor showed a 75% decrease at 24 hours postprocedure and a 50% decrease at a 3-month follow-up. There were no immediate adverse events.

A Non-Contrast Multi-Parametric MRI Biomarker for Assessment of MR-Guided Focused Ultrasound Thermal Therapies.

OBJECTIVE: We present the development of a non-contrast multi-parametric magnetic resonance (MPMR) imaging biomarker to assess treatment outcomes for magnetic resonance-guided focused ultrasound (MRgFUS) ablations of localized tumors. Images obtained immediately following MRgFUS ablation were inputs for voxel-wise supervised learning classifiers, trained using registered histology as a label for thermal necrosis. METHODS: VX2 tumors in New Zealand white rabbits quadriceps were thermally ablated using an MRgFUS system under 3 T MRI guidance. Animals were re-imaged three days post-ablation and euthanized. Histological necrosis labels were created by 3D registration between MR images and digitized H&E segmentations of thermal necrosis to enable voxel-wise classification of necrosis. Supervised MPMR classifier inputs included maximum temperature rise, cumulative thermal dose (CTD), post-FUS differences in T2-weighted images, and apparent diffusion coefficient, or ADC, maps. A logistic regression, support vector machine, and random forest classifier were trained in red a leave-one-out strategy in test data from four subjects. RESULTS: In the validation dataset, the MPMR classifiers achieved higher recall and Dice than a clinically adopted 240 cumulative equivalent minutes at 43 °C (CEM 43) threshold (0.43) in all subjects. The average Dice scores of overlap with the registered histological label for the logistic regression (0.63) and support vector machine (0.63) MPMR classifiers were within 6% of the acute contrast-enhanced non-perfused volume (0.67). CONCLUSIONS: Voxel-wise registration of MPMR data to histological outcomes facilitated supervised learning of an accurate non-contrast MR biomarker for MRgFUS ablations in a rabbit VX2 tumor model.

Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions of interest. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MRI imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Validation of single reference variable flip angle (SR-VFA) dynamic T1 mapping with T2 * correction using a novel rotating phantom.

PURPOSE: To validate single reference variable flip angle (SR-VFA) dynamic T1 mapping with and without T2 * correction against inversion recovery (IR) T1 measurements. METHODS: A custom cylindrical phantom with three concentric compartments was filled with variably doped agar to produce a smooth spatial gradient of the T1 relaxation rate as a function of angle across each compartment. IR T1 , VFA T1 , and B1 + measurements were made on the phantom before rotation, and multi-echo stack-of-radial dynamic images were acquired during rotation via an MRI-compatible motor. B1 + -corrected SR-VFA and SR-VFA-T2 * T1 maps were computed from the sliding window reconstructed images and compared against rotationally registered IR and VFA T1 maps to determine the percentage error. RESULTS: Both VFA and SR-VFA-T2 * T1 maps fell within 10% of IR T1 measurements for a low rotational speed, with a mean accuracy of 2.3% ± 2.6% and 2.8% ± 2.6%, respectively. Increasing rotational speed was found to decrease the accuracy due to increasing temporal smoothing over ranges where the T1 change had a nonconstant slope. SR-VFA T1 mapping was found to have similar accuracy as the SR-VFA-T2 * and VFA methods at low TEs (˜<2 ms), whereas accuracy degraded strongly with later TEs. T2 * correction of the SR-VFA T1 maps was found to consistently improve accuracy and precision, especially at later TEs. CONCLUSION: SR-VFA-T2 * dynamic T1 mapping was found to be accurate against reference IR T1 measurements within 10% in an agar phantom. Further validation is needed in mixed fat-water phantoms and in vivo.

The influence of bone model geometries on the determination of skull acoustic properties.

In this study, we investigated the impact of various simulated skull bone geometries on the determination of skull speed of sound and acoustic attenuation values via optimization using transmitted pressure amplitudes beyond the bone. Using the hybrid angular spectrum method (HAS), we simulated ultrasound transmission through four model sets of different geometries involving sandwiched layers of diploë and cortical bone in addition to three models generated from CT images of ex-vivo human skull-bones. We characterized cost-function solution spaces for each model and, using optimization, found that when a model possessed appreciable variations in resolvable layer thickness, the predefined attenuation coefficients could be found with low error (RMSE < 0.01 Np/cm). However, we identified a spatial frequency cutoff in the models' geometry beyond which the accuracy of the property determination begins to fail, depending on the frequency of the ultrasound source. There was a large increase in error of the attenuation coefficients determined by the optimization when the variations in layer thickness were above the identified spatial frequency cutoffs, or when the lateral variations across the model were relatively low in amplitude. For our limited sample of three CT-image derived bone models, the attenuation coefficients were determined successfully. The speed of sound values were determined with low error for all models (including the CT-image derived models) that were tested (RMSE < 0.4 m/s). These results illustrate that it is possible to determine the acoustic properties of two-component models when the internal bone structure is taken into account and the structure satisfies the spatial frequency constraints discussed.

Development of an MR-guided focused ultrasound (MRgFUS) lesioning approach for small and deep structures in the rat brain.

Objective: High-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a noninvasive therapy to lesion brain tissue, used clinically in patients and preclinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of ∼0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. Methods: The study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n=7 lesions) was compared to a craniectomy approach (n=22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. Results: Comparing a motorized adjustment system (∼1 mm precision, n=17 lesions) to the motorized system with an added micromanipulator (∼0.1 mm precision, n=14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models.

Magnetic Resonance Imaging of Focused Ultrasound Radiation Force Strain Fields for Discrimination of Solid and Liquid Phases.

OBJECTIVE: Focused ultrasound (FUS) has become a non-invasive option for some surgical procedures, including tumor ablation and thalamotomy. Extension of magnetic resonance (MR) imaging-guided focused ultrasound for ablation of slowly perfused cerebrovascular lesions requires a novel treatment monitoring method that does not rely on thermometry or high-frequency Doppler methods. The goal of this study was to evaluate the sensitivity and specificity of strain estimates based on MR acoustic radiation force imaging (MR-ARFI) for differentiation of solids and liquids. METHODS: Strain fields were estimated in gelatin-based tissue-mimicking focused ultrasound phantoms on the basis of apparent displacement fields measured by MR-ARFI. MR-ARFI and diffusion-weighted imaging (DWI) measurements were made before and after FUS-induced heating to evaluate the performance of displacement, strain and apparent diffusion coefficient (ADC) measurements for the discrimination of solid and liquid phases. RESULTS: As revealed by receiver operating characteristic analyses, axial normal strain and shear strain components performed significantly better than axial displacement measurements alone when predicting whether a gelatin had melted. Additional measurements must be made to estimate certain strain components, so this trade-off must be considered when developing clinical strategies. ADC had the best overall performance, but DWI is vulnerable to signal dropouts and susceptibility artifacts near cerebrovascular lesions, so this metric may have limited clinical applicability. CONCLUSION: Strain components based on MR-ARFI apparent displacement measurements perform better than apparent displacement measurements alone at discriminating between solids and liquids. These methods are applicable to FUS treatment monitoring and evaluation of mechanical tissue properties in vivo.

Sustained modulation of primate deep brain circuits with focused ultrasonic waves.

BACKGROUND: Transcranial focused ultrasound has the potential to noninvasively modulate deep brain circuits and impart sustained, neuroplastic effects. OBJECTIVE: Bring the approach closer to translations by demonstrating sustained modulation of deep brain circuits and choice behavior in task-performing non-human primates. METHODS: Low-intensity transcranial ultrasound of 30 s in duration was delivered in a controlled manner into deep brain targets (left or right lateral geniculate nucleus; LGN) of non-human primates while the subjects decided whether a left or a right visual target appeared first. While the animals performed the task, we recorded intracranial EEG from occipital screws. The ultrasound was delivered into the deep brain targets daily for a period of more than 6 months. RESULTS: The brief stimulation induced effects on choice behavior that persisted up to 15 minutes and were specific to the sonicated target. Stimulation of the left/right LGN increased the proportion of rightward/leftward choices. These effects were accompanied by an increase in gamma activity over visual cortex. The contralateral effect on choice behavior and the increase in gamma, compared to sham stimulation, suggest that the stimulation excited the target neural circuits. There were no detrimental effects on the animals' discrimination performance over the months-long course of the stimulation. CONCLUSION: This study demonstrates that brief, 30-s ultrasonic stimulation induces neuroplastic effects specifically in the target deep brain circuits, and that the stimulation can be applied daily without detrimental effects. These findings encourage repeated applications of transcranial ultrasound to malfunctioning deep brain circuits in humans with the goal of providing a durable therapeutic reset.

Influence of cerebrospinal fluid on power absorption during transcranial magnetic resonance-guided focused ultrasound treatment.

BACKGROUND: Ultrasound beam aberration correction is vital when focusing ultrasound through the skull bone in transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) applications. Current methods make transducer element phase adjustments to compensate for the variation in skull properties (shape, thickness, and acoustic properties), but do not account for variations in the internal brain anatomy. PURPOSE: Our objective is to investigate the effect of cerebrospinal fluid (CSF) and brain anatomy on beam focusing in tcMRgFUS treatments. METHODS: Simulations were conducted with imaging data from 20 patients previously treated with focused ultrasound for disabling tremor. The Hybrid Angular Spectrum (HAS) method was used to test the effect of including cerebral spinal fluid (CSF) and brain anatomy in determining the element phases used for aberration correction and beam focusing. Computer tomography (CT) and magnetic resonance imaging (MRI) images from patient treatments were used to construct a segmented model of each patient's head. The segmented model for treatment simulation consisted of water, skin, fat, brain, CSF, diploë, and cortical bone. Transducer element phases used for treatment simulation were determined using time reversal from the desired focus, generating a set of phases assuming a homogeneous brain in the intracranial volume, and a second set of phases assigning CSF acoustic properties to regions of CSF. In addition, for three patients, the relative effect of separately including CSF speed of sound values compared to CSF attenuation values was found. RESULTS: We found that including CSF acoustic properties (speed of sound and attenuation) during phase planning compared to phase correction without considering CSF increased the absorbed ultrasound power density ratios at the focus over a range of 1.06 to 1.29 (mean of 17% ± 6%) for 20 patients. Separately considering the CSF speed of sound and CSF attenuation showed that the increase was due almost entirely to including the CSF speed of sound; considering only the CSF attenuation had a negligible effect. CONCLUSIONS: Based on HAS simulations, treatment planning phase determination using morphologically realistic CSF and brain anatomy yielded an increase of up to 29% in the ultrasound focal absorbed power density. Future work will be required to validate the CSF simulations.

Characterization of susceptibility artifacts in magnetic resonance thermometry images during laser interstitial thermal therapy: dimension analysis and temperature error estimation.

Objective.Laser interstitial thermal therapy (LITT) is a minimally invasive procedure used to treat a lesion through light irradiation and consequent temperature increase. Magnetic resonance thermometry imaging (MRTI) provides a multidimensional measurement of the temperature inside the target, thus enabling accurate monitoring of the damaged zone during the procedure. In proton resonance frequency shift-based thermometry, artifacts in the images may strongly interfere with the estimated temperature maps. In our work, after noticing the formation of the dipolar-behavior artifact linkable to magnetic susceptibility changes duringin vivoLITT, an investigation of susceptibility artifacts in tissue-mimicking phantoms was implemented.Approach.The artifact was characterized: (i) by measuring the area and total volume of error regions and their evolution during the treatment; and (ii) by comparison with temperature reference provided by three temperature sensing needles. Lastly, a strategy to avoid artifacts formation was devised by using the temperature-sensing needles to implement a temperature-controlled LITT.Main results.The artifact appearance was associated with gas bubble formation and with unwanted treatment effects producing magnetic susceptibility changes when 2 W laser power was set. The analysis of the artifact's dimension demonstrated that in the sagittal plane the dipolar-shape artifact may consistently spread following the temperature trend until reaching a volume 8 times bigger than the ablated one. Also, the artifact shape is quite symmetric with respect to the laser tip. An absolute temperature error showing a negative Gaussian profile in the area of susceptibility artifact with values up to 64.4 °C was estimated. Conversely, a maximum error of 2.8 °C is measured in the area not-affected by artifacts and far from the applicator tip. Finally, by regulating laser power, susceptibility artifacts formation was avoided, and appreciable thermal damage was induced.Significance.These findings may help in improving the MRTI-based guidance of thermal therapies.

Simultaneous proton resonance frequency T1 - MR shear wave elastography for MR-guided focused ultrasound multiparametric treatment monitoring.

PURPOSE: To develop an efficient MRI pulse sequence to simultaneously measure multiple parameters that have been shown to correlate with tissue nonviability following thermal therapies. METHODS: A 3D segmented EPI pulse sequence was used to simultaneously measure proton resonance frequency shift (PRFS) MR thermometry (MRT), T1 relaxation time, and shear wave velocity induced by focused ultrasound (FUS) push pulses. Experiments were performed in tissue mimicking gelatin phantoms and ex vivo bovine liver. Using a carefully designed FUS triggering scheme, a heating duty cycle of approximately 65% was achieved by interleaving FUS ablation pulses with FUS push pulses to induce shear waves in the tissue. RESULTS: In phantom studies, temperature increases measured with PRFS MRT and increases in T1 correlated with decreased shear wave velocity, consistent with material softening with increasing temperature. During ablation in ex vivo liver, temperature increase measured with PRFS MRT initially correlated with increasing T1 and decreasing shear wave velocity, and after tissue coagulation with decreasing T1 and increasing shear wave velocity. This is consistent with a previously described hysteresis in T1 versus PRFS curves and increased tissue stiffness with tissue coagulation. CONCLUSION: An efficient approach for simultaneous and dynamic measurements of PRSF, T1 , and shear wave velocity during treatment is presented. This approach holds promise for providing co-registered dynamic measures of multiple parameters, which correlates to tissue nonviability during and following thermal therapies, such as FUS.

Validation of a drift-corrected 3D MR temperature imaging sequence for breast MR-guided focused ultrasound treatments.

Real-time temperature monitoring is critical to the success of thermally ablative therapies. This work validates a 3D thermometry sequence with k-space field drift correction designed for use in magnetic resonance-guided focused ultrasound treatments for breast cancer. Fiberoptic probes were embedded in tissue-mimicking phantoms, and temperature change measurements from the probes were compared with the magnetic resonance temperature imaging measurements following heating with focused ultrasound. Precision and accuracy of measurements were also evaluated in free-breathing healthy volunteers (N = 3) under a non-heating condition. MR temperature measurements agreed closely with those of fiberoptic probes, with a 95% confidence interval of measurement difference from -2.0 °C to 1.4 °C. Field drift-corrected measurements in vivo had a precision of 1.1 ± 0.7 °C and were accurate within 1.3 ± 0.9 °C across the three volunteers. The field drift correction method improved precision and accuracy by an average of 46 and 42%, respectively, when compared to the uncorrected data. This temperature imaging sequence can provide accurate measurements of temperature change in aqueous tissues in the breast and support the use of this sequence in clinical investigations of focused ultrasound treatments for breast cancer.

Remus: System for remote deep brain interventions.

Transcranial-focused ultrasound brings personalized medicine to the human brain. Ultrasound can modulate neural activity or release drugs in specific neural circuits but this personalized approach requires a system that delivers ultrasound into specified targets flexibly and on command. We developed a remote ultrasound system (Remus) that programmatically targets deep brain regions with high spatiotemporal precision and in a multi-focal manner. We validated these functions by modulating two deep brain nuclei-the left and right lateral geniculate nucleus-in a task-performing nonhuman primate. This flexible system will enable researchers and clinicians to diagnose and treat specific deep brain circuits in a noninvasive yet targeted manner, thus embodying the promise of personalized treatments of brain disorders.

Analysis of cavitation artifacts in Magnetic Resonance Imaging Thermometry during laser ablation monitoring.

Magnetic Resonance Thermometry Imaging (MRTI) holds great potential in laser ablation (LA) monitoring. It provides the real-time multidimensional visualization of the treatment effect inside the body, thus enabling accurate intraoperative prediction of the thermal damage induced. Despite its great potential., thermal maps obtained with MRTI may be affected by numerous artifacts. Among the sources of error producing artifacts in the images., the cavitation phenomena which could occur in the tissue during LA induces dipole-structured artifacts. In this work., an analysis of the cavitation artifacts occurring during LA in a gelatin phantom in terms of symmetry in space and symmetry of temperature values was performed. Results of 2 Wand 4 W laser power were compared finding higher symmetry for the 2 W case in terms of both dimensions of artifact-lobes and difference in temperature values extracted in specular pixels in the image. This preliminary investigation of artifact features may provide a step forward in the identification of the best strategy to correct and avoid artifact occurrence during thermal therapy monitoring. Clinical Relevance- This work presents an analysis of cavitation artifacts in MRTI from LA which must be corrected to avoid error in the prediction of thermal damage during LA monitoring.

A k-space-based method to measure and correct for temporal B0 field variations in MR temperature imaging.

PURPOSE: Present a method to use change in phase in repeated Cartesian k-space measurements to monitor the change in magnetic field for dynamic MR temperature imaging. METHODS: The method is applied to focused ultrasound heating experiments in a gelatin phantom and an ex vivo salt pork sample, without and with simulated respiratory motion. RESULTS: In each experiment, phase variations due to B0 field drift and respiration were readily apparent in the measured phase difference. With correction, the SD of the temperature over time was reduced from 0.18°C to 0.14°C (no breathing) and from 0.81°C to 0.22°C (with breathing) for the gelatin phantom, and from 0.68°C to 0.13°C (no breathing) and from 1.06°C to 0.17°C (with breathing) for the pork sample. The accuracy in nonheated regions, assessed as the RMS error deviation from 0°C, improved from 1.70°C to 1.11°C (no breathing) and from 4.73°C to 1.47°C (with breathing) for the gelatin phantom, and from 5.95°C to 0.88°C (no breathing) and from 13.40°C to 1.73°C (with breathing) for the pork sample. The correction did not affect the temperature measurement accuracy in the heated regions. CONCLUSION: This work demonstrates that phase changes resulting from variations in B0 due to drift and respiration, commonly seen in MR thermometry applications, can be measured directly from 3D Cartesian acquisition methods. The correction of temporal field variations using the presented technique improved temperature accuracy, reduced variability in nonheated regions, and did not reduce accuracy in heated regions.

Effects of T2 * on accuracy and precision of dynamic T1 measurements using the single reference variable flip angle method: a simulation study.

PURPOSE: To study in simulation and in theory the accuracy and precision of dynamic T1 measurements obtained using the previously published single-reference variable flip angle (SR-VFA) technique, with a focus on the effects of dynamic changes in T2 * on the calculation. METHODS: Monte Carlo simulations were performed over 1000 noisy iterations for the VFA method, the SR-VFA method, and a proposed method, SR-VFA with a T2 * correction (SR-VFA-T2 *). Dynamic T1 estimates were calculated analytically for each method, with signals modeled by the steady-state spoiled gradient echo equation. The mean and standard deviation of these estimates were calculated and compared to truth, while varying repetition time (TR), baseline and dynamic T1 , echo time (TE), baseline and dynamic T2 *, flip angles, and the number of averages on baseline scans. Additionally, the variance of T1 in the SR-VFA and SR-VFA-T2 * methods was derived analytically based on the theory of propagation of errors. This equation was used to produce an inverse-variance weighted linear combination to improve T1 mapping precision in the SR-VFA-T2 * method. Flip angle sensitivity of dynamic T1 precision in the SR-VFA and SR-VFA-T2 * methods was also performed. RESULTS: Substantial bias can be produced by the SR-VFA method when the ratio of the T2 * decay of the dynamic signal versus that of the baseline signals deviates from 1, with a 0.01 deviation leading to approximately a 1% bias in cases of high SNR and TR ≫ T1 . This bias can be corrected by estimating the baseline and dynamic T2 * values in this ratio via multiecho measurements. The bias and precision of the SR-VFA-T2 * method, when normalized to scan time, is found to rival and sometimes improve upon the two flip angle VFA method when an inverse variance weighted linear combination is applied across its multiecho T1 maps. The analytic variance equation presented is found to be accurate within 1% relative to the Monte Carlo simulations over a broad parameter space. Flip angle ranges that maximize SR-VFA and SR-VFA-T2 *T1 precision over a broad parameter space are given, and each is defined relative to TR and T1 . CONCLUSIONS: Multiecho SR-VFA-T2 * T1 mapping is found in simulation and theory to be a promising alternative to the VFA method that maintains speed of the SR-VFA method with accuracy and precision similar to the VFA method.

Histology to 3D in vivo MR registration for volumetric evaluation of MRgFUS treatment assessment biomarkers.

Advances in imaging and early cancer detection have increased interest in magnetic resonance (MR) guided focused ultrasound (MRgFUS) technologies for cancer treatment. MRgFUS ablation treatments could reduce surgical risks, preserve organ tissue and function, and improve patient quality of life. However, surgical resection and histological analysis remain the gold standard to assess cancer treatment response. For non-invasive ablation therapies such as MRgFUS, the treatment response must be determined through MR imaging biomarkers. However, current MR biomarkers are inconclusive and have not been rigorously evaluated against histology via accurate registration. Existing registration methods rely on anatomical features to directly register in vivo MR and histology. For MRgFUS applications in anatomies such as liver, kidney, or breast, anatomical features that are not caused by the treatment are often insufficient to drive direct registration. We present a novel MR to histology registration workflow that utilizes intermediate imaging and does not rely on anatomical MR features being visible in histology. The presented workflow yields an overall registration accuracy of 1.00 ± 0.13 mm. The developed registration pipeline is used to evaluate a common MRgFUS treatment assessment biomarker against histology. Evaluating MR biomarkers against histology using this registration pipeline will facilitate validating novel MRgFUS biomarkers to improve treatment assessment without surgical intervention. While the presented registration technique has been evaluated in a MRgFUS ablation treatment model, this technique could be potentially applied in any tissue to evaluate a variety of therapeutic options.