Effect of reducing isoflurane level on glucosamine uptake in the mouse brain during magnetic resonance imaging studies.

Anesthesia is often required during magnetic resonance imaging (MRI) examinations in animal studies. Anesthetic drugs differ in their capacity to interfere with homeostatic mechanisms responsible for glucose metabolism in the brain, which may create a constraint in the study design. Recent studies suggest that the chemical exchange saturation transfer (CEST) MRI scanning technique can detect localized metabolic changes in rodent brains induced by the uptake of glucose or its analogs; however, most of these studies do not account for the impact of anesthesia type on the brain metabolism. Herein, we aimed to evaluate the effect of reduced isoflurane levels on the preclinical imaging of glucosamine (GlcN) uptake in healthy mouse brains to establish optimal conditions for future brain imaging studies using the CEST MRI technique. The commonly used anesthesia protocol for longitudinal MRI examinations using 1.5% isoflurane level was compared to that using a mixture of low isoflurane (0.8%) level combined with midazolam (2 mg/kg, SC). Magnetization transfer ratio asymmetry (MTRasym) and area under the curve (AUC) analyses were used to characterize GlcN signals in the brain. The results indicated that mice injected with GlcN and anesthetized with 1.5% isoflurane exhibited low and insignificant changes in the MTRasym and AUC signals in the frontal cortex, whereas mice administered with 0.8% isoflurane combined with midazolam demonstrated a significant increase in these signals in the frontal cortex. This study highlights the diverse GlcN metabolic changes observed in mouse brains under variable levels of isoflurane anesthesia using the CEST MRI method. The results suggest that it is feasible to maintain anesthesia with low-dose isoflurane by integrating midazolam, which may enable the investigation of GlcN uptake in the brain. Thus, reducing isoflurane levels may support studies into mouse brain metabolism using the CEST MRI method and should be considered in future studies.

Quantitative Magnetization EXchange MRI Measurement of Liver Fibrosis Model in Rodents.

BACKGROUND: Quantitative MRI can elucidate the complex microstructural changes in liver disease. The Magnetization EXchange (MEX) method estimates macromolecular fraction, such as collagen, and can potentially aid in this task. HYPOTHESIS: MEX sequence, and its derived quantitative macromolecular fraction, should correlate with collagen deposition in rodents liver fibrosis model. STUDY TYPE: Prospective. ANIMAL MODEL: Sixteen adults Sprague-Dawley rats and 13 adults C57BL/6 strain mice given carbon tetrachloride (CCl4 ) twice weekly for 6 or 8 weeks. FIELD STRENGTH/SEQUENCE: A 7 T scanner. MEX sequence (selective suppression and magnetization exchange), spin-echo and gradient-echo scans. ASSESSMENT: Macromolecular fraction (F) and T1 were extracted for each voxel and for livers' regions of interest, additional to calculating the percentage of F > 0.1 pixels in F maps (high-F). Histology included staining with hematoxylin and eosin, picrosirius red and Masson trichrome, and inflammation scoring. Quantitative collagen percentage calculated using automatic spectral-segmentation of the staining. STATISTICAL TESTS: Comparing CCl4 -treated groups and controls using Welch's t-test and paired t-test between different time points. Pearson's correlation used between ROI MEX parameters or high-F fraction, and quantitative histology. F or T1 , and inflammation scores were tested with one-sided t-test. P < 0.05 was deemed significant. RESULTS: Rats: F values were significantly different after 6 weeks of treatment (0.10 ± 0.02) compared to controls (0.080 ± 0.003). After 8 weeks, F significantly increased (0.11 ± 0.02) in treated animals, while controls are not significant (0.0814 ± 0.0008, P = 0.079). F correlated with quantitative histology (R = 0.87), and T1 was significantly different between inflammation scores (1: 1332 ± 224 msec, 2: 2007 ± 464 msec). Mice: F was significantly higher (0.062 ± 0.006) in treatment group compared to controls (0.042 ± 0.006). F and high-F fraction correlated with quantitative histology (R = 0.88; R = 0.84). T1 was significantly different between inflammation scores (1:1366 ± 99 msec; 2:1648 ± 45 msec). DATA CONCLUSION: MEX extracted parameters are sensitive to collagen deposition and inflammation and are correlated with histology results of mouse and rat liver fibrosis model. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Breast cancer imaging with glucosamine CEST (chemical exchange saturation transfer) MRI: first human experience.

OBJECTIVES: This study aims to evaluate the feasibility of imaging breast cancer with glucosamine (GlcN) chemical exchange saturation transfer (CEST) MRI technique to distinguish between tumor and surrounding tissue, compared to the conventional MRI method. METHODS: Twelve patients with newly diagnosed breast tumors (median age, 53 years) were recruited in this prospective IRB-approved study, between August 2019 and March 2020. Informed consent was obtained from all patients. All MRI measurements were performed on a 3-T clinical MRI scanner. For CEST imaging, a fat-suppressed 3D RF-spoiled gradient echo sequence with saturation pulse train was applied. CEST signals were quantified in the tumor and in the surrounding tissue based on magnetization transfer ratio asymmetry (MTRasym) and a multi-Gaussian fitting. RESULTS: GlcN CEST MRI revealed higher signal intensities in the tumor tissue compared to the surrounding breast tissue (MTRasym effect of 8.12 ± 4.09%, N = 12, p = 2.2 E-03) with the incremental increase due to GlcN uptake of 3.41 ± 0.79% (N = 12, p = 2.2 E-03), which is in line with tumor location as demonstrated by T1W and T2W MRI. GlcN CEST spectra comprise distinct peaks corresponding to proton exchange between free water and hydroxyl and amide/amine groups, and relayed nuclear Overhauser enhancement (NOE) from aliphatic groups, all yielded larger CEST integrals in the tumor tissue after GlcN uptake by an averaged factor of 2.2 ± 1.2 (p = 3.38 E-03), 1.4 ± 0.4 (p =9.88 E-03), and 1.6 ± 0.6 (p = 2.09 E-02), respectively. CONCLUSION: The results of this initial feasibility study indicate the potential of GlcN CEST MRI to diagnose breast cancer in a clinical setup. KEY POINTS: • GlcN CEST MRI method is demonstrated for its the ability to differentiate between breast tumor lesions and the surrounding tissue, based on the differential accumulation of the GlcN in the tumors. • GlcN CEST imaging may be used to identify metabolic active malignant breast tumors without using a Gd contrast agent. • The GlcN CEST MRI method may be considered for use in a clinical setup for breast cancer detection and should be tested as a complementary method to conventional clinical MRI methods.

An in vivo implementation of the MEX MRI for myelin fraction of mice brain.

OBJECTIVE: Magnetization EXchange (MEX) sequence measures a signal linearly dependent on the myelin proton fraction by selective suppression of water magnetization and a recovery period. Varying the recovery period enables extraction of the percentile fraction of myelin bound protons. We aim to demonstrate the MEX sequence sensitivity to the fraction of protons associated with myelin in mice brain, in vivo. METHODS: The cuprizone mouse model was used to manipulate the myelin content. Mice fed cuprizone (n = 15) and normal chow (n = 8) were imaged in vivo using MEX sequence. MR images were segmented into corpus callosum and internal capsule (white matter) and cortical gray matter, and fitted to the recovery equation. Results were analyzed with correlation to MWF and histopathology. RESULTS: The extracted parameters show significant differences in the corpus callosum between the cuprizone and control groups. The cuprizone group exhibited reduced myelin fraction 26.5% (P < 0.01). The gray matter values were less affected, with 13.5% reduction (P < 0.05); no changes were detected in the internal capsule. Results were validated by MWF scans and good correlation to the histology analysis (R2 = 0.685). CONCLUSION: The results of this first in vivo implementation of the MEX sequence provide a quantitative measure of demyelination in brain white matter.

What do we know about dynamic glucose-enhanced (DGE) MRI and how close is it to the clinics? Horizon 2020 GLINT consortium report.

Cancer is one of the most devastating diseases that the world is currently facing, accounting for 10 million deaths in 2020 (WHO). In the last two decades, advanced medical imaging has played an ever more important role in the early detection of the disease, as it increases the chances of survival and the potential for full recovery. To date, dynamic glucose-enhanced (DGE) MRI using glucose-based chemical exchange saturation transfer (glucoCEST) has demonstrated the sensitivity to detect both D-glucose and glucose analogs, such as 3-oxy-methyl-D-glucose (3OMG) uptake in tumors. As one of the recent international efforts aiming at pushing the boundaries of translation of the DGE MRI technique into clinical practice, a multidisciplinary team of eight partners came together to form the "glucoCEST Imaging of Neoplastic Tumors (GLINT)" consortium, funded by the Horizon 2020 European Commission. This paper summarizes the progress made to date both by these groups and others in increasing our knowledge of the underlying mechanisms related to this technique as well as translating it into clinical practice.

Molecular imaging of cancer by glucosamine chemical exchange saturation transfer MRI: A preclinical study.

Glucosamine (GlcN) was recently proposed as an agent with an excellent safety profile to detect cancer with the chemical exchange saturation transfer (CEST) MRI technique. Translation of the GlcN CEST method to the clinical application requires evaluation of its sensitivity to the different frequency regions of irradiation. Hence, imaging of the GlcN signal was established for the full Z spectra recorded following GlcN administration to mice bearing implanted 4T1 breast tumors. Significant CEST effects were observed at around 1.5, 3.6 and -3.4 ppm, corresponding to the hydroxyl, amine/amide exchangeable protons and for the Nuclear Overhauser Enhancement (NOE), respectively. The sources of the observed CEST effects were investigated by identifying the GlcN metabolic products as observed by 13 C NMR spectroscopy studies of extracts from the same tumor model following treatment with [UL-13 C] -GlcN·HCl. The CEST contribution can be attributed to several phosphorylated products of GlcN, including uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is a substrate for the O-linked and N-linked glycosylated proteins that may be associated with the increase of the NOE signal. The observation of a significant amount of lactate among the metabolic products hints at acidification as one of the sources of the enhanced CEST effect of GlcN. The proposed method may offer a new approach for clinical molecular imaging that enables the detection of metabolically active tumors and may play a role in other diseases.

Identification of water compartments in spinal cords by 2 H double quantum filtered NMR.

In 2 H double quantum filtered (DQF) NMR, the various water compartments are characterized by their different residual quadrupolar interactions. The spectral separation between the different signals enables the measurement of the relaxation of each compartment and the magnetization transfer (MT) between them. In the current study, five water compartments were identified in the 2 H DQF spectra of porcine spinal cord. The most prominent signal was the pair of satellites with a quadrupolar splitting of about 550 Hz. 2 H DQF MRI optimized for the 550 Hz quadrupolar splitting indicated that this signal originated mainly from the white matter and it was assigned to the myelin water. This splitting does not change upon changing the orientation of the spinal cord relative to the magnetic field, indicating a liquid crystalline nature. Another site exhibiting splitting of about 1500 Hz was assigned to collagenous connective tissue. The narrow central peak was assigned to a combination of intra- and inter-axonal water. The assignment of the other two sites is not certain and requires further study. The rates of MT between the various sites were recorded.

Deuterium double quantum-filtered NMR studies of peripheral and optic nerves.

OBJECTIVE: Characterization of the nerve components by deuterium double quantum-filtered magnetization transfer (DQF-MT) NMR. METHODS: Nerves were equilibrated in deuterated saline and 2H single-pulse and 2H DQF-MT NMR spectra were measured, enabling the separation of the different water compartments, according to their quadrupolar splittings. RESULTS: Rat sciatic and brachial nerves and porcine optic nerve immersed in deuterated saline yielded 2H DQF spectra composed of three pairs of quadrupolar-split signals assigned to the water in the collagenous compartments and the myelin bilayer and one narrow signal assigned to the axonal water. Stretching of the nerves, application of osmotic stress and incubation in collagenase did not affect the quadrupolar splitting of the myelin water. The signals of myelin and axonal water were shown to decay during Wallerian degeneration and to rise during maturation. The chemical exchange between the myelin and the intra-axonal water was measured for optic nerve during maturation. The quadrupolar splitting of the signal of myelin water was not sensitive to its orientation relative to the magnetic field. This resembles liquid crystalline behavior, but leaves its mechanism open for interpretation. CONCLUSIONS: 2H DQF-MT NMR characterizes the different components of nerves, the water exchange between them and their changes during processes such as nerve maturation and Wallerian degeneration.

New insight into the organization of myelin water using deuterium NMR.

PURPOSE: Myelin water is commonly characterized by its short proton T2 relaxation time, suggesting strong association with the polar head groups of the bilayer constituents. Deuterium NMR of water in ordered structures exhibits splittings as a result of quadrupolar interactions that are observable using the double-quantum filter. The purpose of the current study was to identify and characterize the water populations. METHODS: The 2 H double-quantum-filtered spectroscopic experiments were conducted at 62 MHz (9.4 T) on a sample of reconstituted myelin from ovine spinal cord after exchange of native water with D2 O. RESULTS: Signals passing the double-quantum filter were attributed to 2 water pools: 1 consisting of a doublet of 650-Hz splitting, and a second unsplit signal. Similar signals were observed in the sciatic and optic nerves and in the spinal cord. Further, data suggest that diffusion of water molecules in these 2 pools (Dapp  ≤ 5 × 10-7  cm2 /s) is either hindered or restricted. An estimate of exchange lifetime of 10-15 ms between water pertaining to the single peak and that of the split peaks suggests exchange occurs in a slow-intermediate rate regime. Further distinction between the 2 pools was obtained from T1 measurements. Deuterons belonging to the doublet resonance were found to have short T1 , estimated to be on the order of 10-20 ms, whereas those corresponding to the single peak were close to that of bulk D2 O. CONCLUSION: The results suggest that myelin extract water consists of 2 hindered populations with distinct degrees of anisotropic motion that can be studied by 2 H double-quantum-filtered NMR.

Quantification of hydroxyl exchange of D-Glucose at physiological conditions for optimization of glucoCEST MRI at 3, 7 and 9.4 Tesla.

AIMS: To determine individual glucose hydroxyl exchange rates at physiological conditions and use this information for numerical optimization of glucoCEST/CESL preparation. To give guidelines for in vivo glucoCEST/CESL measurement parameters at clinical and ultra-high field strengths. METHODS: Five glucose solution samples at different pH values were measured at 14.1 T at various B1 power levels. Multi-B1 -Z-spectra Bloch-McConnell fits at physiological pH were further improved by the fitting of Z-spectra of five pH values simultaneously. The obtained exchange rates were used in a six-pool Bloch-McConnell simulation including a tissue-like water pool and semi-solid MT pool with different CEST and CESL presaturation pulse trains. In vivo glucose injection experiments were performed in a tumor mouse model at 7 T. RESULTS AND DISCUSSION: Glucose Z-spectra could be fitted with four exchanging pools at 0.66, 1.28, 2.08 and 2.88 ppm. Corresponding hydroxyl exchange rates could be determined at pH = 7.2, T = 37°C and 1X PBS. Simulation of saturation transfer for this glucose system in a gray matter-like and a tumor-like system revealed optimal pulses at different field strengths of 9.4, 7 and 3 T. Different existing sequences and approaches are simulated and discussed. The optima found could be experimentally verified in an animal model at 7 T. CONCLUSION: For the determined fast exchange regime, presaturation pulses in the spin-lock regime (long recover time, short yet strong saturation) were found to be optimal. This study gives an estimation for optimization of the glucoCEST signal in vivo on the basis of glucose exchange rate at physiological conditions.

3-O-Methyl-D-glucose mutarotation and proton exchange rates assessed by 13C, 1H NMR and by chemical exchange saturation transfer and spin lock measurements.

3-O-Methyl-D-glucose (3OMG) was recently suggested as an agent to image tumors using chemical exchange saturation transfer (CEST) MRI. To characterize the properties of 3OMG in solution, the anomeric equilibrium and the mutarotation rates of 3OMG were studied by 1H and 13C NMR. This information is essential in designing the in vivo CEST experiments. At room temperature, the ratio of α and ß 3OMG anomers at equilibrium was 1:1.4, and the time to reach 95% equilibrium was 6 h. The chemical exchange rates between the hydroxyl protons of 3OMG and water, measured by CEST and spin lock at pH 6.14 and a temperature of 4 °C, were in the range of 360-670 s-1.

CEST MRI of 3-O-methyl-D-glucose on different breast cancer models.

PURPOSE: To test the ability of chemical exchange saturation transfer (CEST) MRI of 3-O-methyl-D-glucose (3OMG) to detect tumors in several breast cancer models of murine and human origin, for different routes of administration of the agent and to compare the method with glucoCEST and with 18 FDG-PET on the same animals. METHODS: In vivo CEST MRI experiments were performed with a 7T Biospec animal MRI scanner on implanted orthotopic mammary tumors of mice before and after administration of 3OMG. RESULTS: A marked 3OMG-CEST MRI contrast that was correlated with the administrated dose was obtained in different breast cancer models and by intravenous, intraperitoneal, and per os methods of administration. The most aggressive breast cancer model yielded the highest CEST contrast. 3OMG-CEST contrast reached its maximum at 20 min after administration and lasted for more than an hour, while that of glucose was lower and diminished after 20 min. 3OMG-CEST showed comparable results to that of FDG PET. CONCLUSION: The sensitivity of the 3OMG-CEST MRI method indicates its potential for the detection of tumors in the clinic. Magn Reson Med 79:1061-1069, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

In vivo assessment of aged human skin with a unilateral NMR scanner.

Human skin undergoes morphological and biochemical changes as a result of chronological aging and exposure to solar ultraviolet irradiation (photoaging). Noninvasive detection of these changes may aid in the prevention and treatment of both types of aging. This article presents a noninvasive method for the evaluation of aging skin with a unilateral stray field NMR scanner. These portable and inexpensive scanners may be suitable for in-depth skin characterization. In vivo profiles of sun-protected and sun-exposed skin from the forearms of female subjects of different ages (n = 9) were measured. Skin biopsies for histopathological examination were used as reference. T2 analysis with a bi-exponential decay model was applied and the extracted parameters were examined as markers for dermal aging. In the upper reticular dermis, a significant increase in the fraction of the slow T2 component and in the T2 value itself was found to correlate with chronological aging. For most subjects, there was an additional increase in the values of the slow T2 component and the T2 values from the sun-exposed forearm, superimposed on that measured for the sun-protected forearm. These results are in agreement with the decline in collagen content and the increase in free water content with aging. The results suggest that such a technique can be used as a tool for the assessment of aging, and that bi-exponential fitting can produce sensitive fingerprint parameters for the dermal alterations that occur during aging.

Functional molecular imaging of tumors by chemical exchange saturation transfer MRI of 3-O-Methyl-D-glucose.

PURPOSE: To evaluate the feasibility to detect tumors and metastases by the chemical exchange saturation transfer (CEST) MRI technique using 3-O-Methyl-D-glucose (3OMG), a nonmetabolizable derivative of glucose that is taken up rapidly and preferentially by tumors and is entirely excreted by the kidneys. METHODS: In vivo CEST MRI experiments were performed on a Bruker 7 Tesla Biospec on implanted orthotopic mammary tumors of mice before and following i.p. injection of 3OMG. The CEST images were generated by a series of gradient-echo images collected from a single 1 mm coronal slice after a 1.2 s presaturation pulse, applied at offsets of ±1.2 ppm from the water and at B(1) power of 2.5 µT. RESULTS: Following 3OMG (1.5 g/kg) i.p. injection, an enhanced CEST effect of approximately 20% was visualized at the tumor within a few minutes. The signal slowly declined reaching half of its maximum at approximately 80 min. CONCLUSION: Due to the large CEST effect of 3OMG and its low toxicity 3OMG-CEST may serve for the detection of tumors and metastases in the clinic.

Collagen composition and content-dependent contrast in porcine annulus fibrosus achieved by using double quantum and magnetization transfer filtered UTE MRI.

PURPOSE: To test the potential of combining double quantum and magnetization transfer filtered ultra-short echo time (DQF-MT-UTE) MRI to obtain information about the macromolecular composition and characteristics of connective tissues. METHODS: A DQF-MT-UTE pulse sequence was implemented on a 14.1 T AVANCE III Bruker spectrometer equipped with a Bruker micro2.5-imaging gradient system to obtain images of porcine annulus fibrosus. RESULTS: The DQF-MT-UTE MRI of the annulus fibrosus of porcine intervertebral disc, where the creation time of the double quantum coherence filtering (DQF) was on a time scale appropriate for excitation of macromolecules, showed stronger signal from the outer layers of the disc than from the inner layers closer to the nucleus pulposus. Similarly, spectroscopic studies showed the same trend in the efficiency of the magnetization transfer (MT) from collagen to water. CONCLUSION: DQF-MT filtered UTE MRI of the annulus fibrosus provides new contrast parameters that depend on the concentration of the collagen and on the rate and efficiency of MT of its protons to water. The latter parameters appear to be different for collagen types I and II in the annulus fibrosus.

DQF-MT MRI of connective tissues: application to tendon and muscle.

OBJECT: The sequence combining DQF (double quantum filtering) with magnetisation transfer (DQF-MT) was tested as an alternative to the DQF sequence for characterising tendon and muscle by MR imaging. MATERIALS AND METHODS: DQF-MT images of tendon-muscle phantoms were obtained at 4.7 T using ultra-short time to echo (UTE) methods in order to alleviate the loss of SNR due to the short T2 of the tissues. Two different sampling schemes of the k-space, Cartesian or radial, were employed. In vivo images of the human ankle on a clinical 1.5 T scanner are also presented. Parameters providing optimal tendon signal as well as optimal contrast between this tissue and muscle were determined. RESULTS: Two sets of parameters resulting in different contrasts between the tissues were found. For the first set (short creation time τ = 10 µs and magnetisation exchange time t LM = 100 ms), DQF-MT signals in muscle and tendon were detected, with that of the tendon being the larger one. For the second set (long creation time τ = 750 µs and magnetisation exchange time 10 µs < t LM < 100 ms), the DQF-MT signal was detected only in the tendon, and the decay of the double quantum coherence was slower than that observed for the first one, which allowed us to acquire DQF-MT MR images on a clinical 1.5 T MR scanner with minimal software interventions. In favourable conditions, the DQF-MT signal in the tendon could represent up to 10 % of the single-quantum signal. CONCLUSION: Dipolar interaction within macromolecules such as collagen and myosin is at the origin of the DQF-MT signal observed in the first parameter set. This should enable the detection of muscle fibrosis.

Metabolic brain imaging with glucosamine CEST MRI: in vivo characterization and first insights.

The utility of chemical exchange saturation transfer (CEST) MRI for monitoring the uptake of glucosamine (GlcN), a safe dietary supplement, has been previously demonstrated in detecting breast cancer in both murine and human subjects. Here, we studied and characterized the detectability of GlcN uptake and metabolism in the brain. Following intravenous GlcN administration in mice, CEST brain signals calculated by magnetization transfer ratio asymmetry (MTRasym) analysis, were significantly elevated, mainly in the cortex, hippocampus, and thalamus. The in vivo contrast remained stable during 40 min of examination, which can be attributed to GlcN uptake and its metabolic products accumulation as confirmed using 13C NMR spectroscopic studies of brain extracts. A Lorentzian multi-pool fitting analysis revealed an increase in the hydroxyl, amide, and relayed nuclear Overhauser effect (rNOE) signal components after GlcN treatment. With its ability to cross the blood-brain barrier (BBB), the GlcN CEST technique has the potential to serve as a metabolic biomarker for the diagnosis and monitoring various brain disorders.

Characterization and mapping of dipolar interactions within macromolecules in tissues using a combination of DQF, MT and UTE MRI.

This study shows that by combining a double-quantum filtered magnetization transfer (DQF-MT) with an ultra-short TE (UTE) MRI that it is possible to obtain contrast between tissue compartments based on the following characteristics: (a) the residual dipolar coupling interaction within the biomacromolecules, which depends on their structure, (b) residual dipolar interactions within water molecules, and (c) the magnetization exchange rate between biomacromolecules and water. The technique is demonstrated in rat-tail specimens, where the collagenous tissue such as tendons and the annulus pulposus of the disc are highlighted in these images, and their macromolecular properties along with those of bones and muscles can be characterized. DQF-MT UTE MRI also holds promise because collagenous tissues that are typically invisible in conventional MRI experiments produce significant signal intensities using this approach.

Assessment of glycosaminoglycan concentration changes in the intervertebral disc via chemical exchange saturation transfer.

In this study, it is shown that the chemical exchange saturation transfer (CEST) method for hydroxyl protons can be used to detect changes in glycosaminoglycan (GAG) concentration in the intervertebral disc. The method, termed gagCEST, was demonstrated ex vivo by correlating the CEST effect with the fixed charge density (FCD) of the nucleus pulposus (NP), as well as by correlating tissue CEST images with their corresponding (23)Na images. Incubation of five NP samples with trypsin produced samples with varying GAG content (n = 19). A good correlation was found between the -OH CEST effect and FCD, as well as with the N-acetyl signal amplitude. gagCEST images in vitro further illustrated the amount of detail obtainable from this contrast mechanism when compared with conventional imaging. The large concentration of GAG and the relatively long T(1) of water in NP make the method sensitive, in particular, for the assessment of GAG depletion in this tissue. It is the loss of GAG in NP that indicates the early stage of disc degeneration.

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound.

PURPOSE: To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. METHODS: The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., "MR-guided adaptive focusing of ultrasound," IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734-1747 (2010)] was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients' phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. RESULTS: Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. CONCLUSIONS: The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy.