2D CAIPI accelerated 3D multi-slab diffusion weighted EPI combined with qModeL reconstruction for fast high resolution microstructure imaging.

PURPOSE: To develop acceleration strategies for 3D multi-slab diffusion weighted imaging (3D ms-DWI) for enabling applications that require simultaneously high spatial (1 mm isotropic) and angular (> 30 directions) resolutions. METHODS: 3D ms-DWI offers high SNR-efficiency, with the ability to achieve high isotropic spatial resolution, yet suffers from long scan-times for studies requiring high angular resolutions. We develop 6D k-q space acceleration strategies to reduce the scan-time. Specifically, we develop non-uniform 3D ky-kz under-sampling employing a shot-selective 2D CAIPI sampling approach. To achieve inter-shot phase-compensation, 2D navigators were employed that utilize the same CAIPI trajectory. An iterative model-based 3D multi-shot reconstruction was designed by incorporating phase into the forward encoding process. Additionally, the shot-selective non-uniform ky-kz CAIPI acceleration was randomized along the q-dimension. The 3D model-based multi-shot reconstruction is then extended to a joint reconstruction that simultaneously reconstructs all the q-space points, with the help of a spatial total variation and deep-learned q-space regularization. RESULTS: The proposed reconstruction is shown to achieve adequate phase-compensation in both 2D CAIPI accelerated and additional ky-kz under-sampled cases. Using retrospective under-sampling experiments, we show that k-q accelerations close a factor of 12 can be achieved with a reconstruction error < 3% for both single and multi-shell data. This translates to a scan-time reduction by 3-fold for experiments with simultaneously high spatial and angular resolutions. CONCLUSION: The proposed method facilitates the utilization of 3D ms-DWI for simultaneously high k-q resolution applications with close to 3× reduced scan-time.

MRI Detection and Therapeutic Enhancement of Ferumoxytol Internalization in Glioblastoma Cells.

Recently, the FDA-approved iron oxide nanoparticle, ferumoxytol, has been found to enhance the efficacy of pharmacological ascorbate (AscH-) in treating glioblastoma, as AscH- reduces the Fe3+ sites in the nanoparticle core. Given the iron oxidation state specificity of T2* relaxation mapping, this study aims to investigate the ability of T2* relaxation to monitor the reduction of ferumoxytol by AscH- with respect to its in vitro therapeutic enhancement. This study employed an in vitro glioblastoma MRI model system to investigate the chemical interaction of ferumoxytol with T2* mapping. Lipofectamine was utilized to facilitate ferumoxytol internalization and assess intracellular versus extracellular chemistry. In vitro T2* mapping successfully detected an AscH--mediated reduction of ferumoxytol (25.6 ms versus 2.8 ms for FMX alone). The T2* relaxation technique identified the release of Fe2+ from ferumoxytol by AscH- in glioblastoma cells. However, the high iron content of ferumoxytol limited T2* ability to differentiate between the external and internal reduction of ferumoxytol by AscH- (ΔT2* = +839% for external FMX and +1112% for internal FMX reduction). Notably, the internalization of ferumoxytol significantly enhances its ability to promote AscH- toxicity (dose enhancement ratio for extracellular FMX = 1.16 versus 1.54 for intracellular FMX). These data provide valuable insights into the MR-based nanotheranostic application of ferumoxytol and AscH- therapy for glioblastoma management. Future developmental efforts, such as FMX surface modifications, may be warranted to enhance this approach further.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.

T2* Imaging Assessment of Neoadjuvant Radiation Therapy Combined With Pharmacological Ascorbate in Extremity Soft-Tissue Sarcomas: A Pilot Study.

Background: Extremity soft-tissue sarcomas (STS) are commonly treated with neoadjuvant radiation therapy followed by surgical resection. However, the pathological near-complete response rate is low (9-25%). Noninvasive imaging assessment that predicts treatment response before and during treatment is desirable to optimize treatment regimens. This pilot study aimed to investigate the application of a quantitative MRI parameter, T2*, in assessing neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Methods: This prospective cohort study included seven patients diagnosed with extremity STS and scheduled to receive neoadjuvant radiation therapy combined with pharmacological ascorbate. T2* maps were obtained from each patient before treatment (baseline MRI), two weeks after initiating treatment (on-treatment MRI), and before surgery (pre-surgery MRI). The T2* values within the tumor region were transformed into z-scores with respect to the normal- appearing tissue region. The voxel-wise z-scores within the tumor region were thresholded to generate masks representing significantly high (z-score>1.96) and low z-score (z-score<-1.96) voxels. The means of the total z-scores and within each of the significantly high and low z-score mask were computed. Their correlations with percent necrosis from pathological examination were evaluated using Spearman's rank correlation coefficient r. A correlation was considered as moderate or strong when r is higher than 0.6 and 0.8, respectively. A correlation was considered as fair or weak when r is below 0.6. Results: For the baseline and on-treatment MRIs, the means of the significantly high z-scores of the T2* measurements showed moderate correlations with percent necrosis (r = 0.68 and 0.6; p = 0.11 and 0.24). For the pre-surgery MRI, the means of the total and significantly high z-scores showed strong correlations with percent necrosis (r = 0.8 and 0.9; p = 0.13 and 0.08). Tumor volume and baseline MRI-based percent necrosis showed fair or weak correlations (r = 0.3-0.54; p = 0.24-0.68). Conclusion: T2* measurements prior to treatment, two weeks after initiating treatment, and before surgery showed moderate to strong correlations with percent necrosis. These results support the potential for using T2* mapping to predict and assess response to neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Level of Evidence: IV.

Reduced Hippocampal Volume and Neurochemical Response to Adult Stress Exposure in a Female Mouse Model of Urogenital Hypersensitivity.

Early life stress exposure significantly increases the risk of developing chronic pain syndromes and comorbid mood and metabolic disorders later in life. Structural and functional changes within the hippocampus have been shown to contribute to many early life stress-related outcomes. We have previously reported that adult mice that underwent neonatal maternal separation (NMS) exhibit urogenital hypersensitivity, altered anxiety- and depression-like behaviors, increased adiposity, and decreased gene expression and neurogenesis in the hippocampus. Here, we are using magnetic resonance imaging and spectroscopy (MRI and MRS) to further investigate both NMS- and acute stress-induced changes in the hippocampus of female mice. Volumetric analysis of the whole brain revealed that the left hippocampus of NMS mice was 0.038 mm3 smaller compared to naïve mice. MRS was performed only on the right hippocampus and both total choline (tCho) and total N-acetylaspartate (tNAA) levels were significantly decreased due to NMS, particularly after WAS. Phosphoethanolamine (PE) levels were decreased in naïve mice after WAS, but not in NMS mice, and WAS increased ascorbate levels in both groups. The NMS mice showed a trend toward increased body weight and body fat percentage compared to naïve mice. A significant negative correlation was observed between body weight and phosphocreatine levels post-WAS in NMS mice, as well as a positive correlation between body weight and glutamine for NMS mice and a negative correlation for naïve mice. Together, these data suggest that NMS in mice reduces left hippocampal volume and may result in mitochondrial dysfunction and reduced neuronal integrity of the right hippocampus in adulthood. Hippocampal changes also appear to be related to whole body metabolic outcomes.

The relationship between diffusion heterogeneity and microstructural changes in high-grade gliomas using Monte Carlo simulations.

PURPOSE: Diffusion-weighted imaging (DWI) may aid accurate tumor grading. Decreased diffusivity and increased diffusion heterogeneity measures have been observed in high-grade gliomas using the non-monoexponential models for DWI. However, DWI measures concerning tissue characteristics in terms of pathophysiological and structural changes are yet to be established. Thus, this study aims to investigate the relationship between the diffusion measurements and microstructural changes in the presence of high-grade gliomas using a three-dimensional Monte Carlo simulation with systematic changes of microstructural parameters. METHODS: Water diffusion was simulated in a microenvironment along with changes associated with the presence of high-grade gliomas, including increases in cell density, nuclear volume, extracellular volume (VFex), and extracellular tortuosity (λex), and changes in membrane permeability (Pmem). DWI signals were simulated using a pulsed gradient spin-echo sequence. The sequence parameters, including the maximum gradient strength and diffusion time, were set to be comparable to those of clinical scanners and advanced human MRI systems. The DWI signals were fitted using the gamma distribution and diffusional kurtosis models with b-values up to 6000 and 2500 s/mm2, respectively. RESULTS: The diffusivity measures (apparent diffusion coefficients (ADC), Dgamma of the gamma distribution model and Dapp of the diffusional kurtosis model) decreased with increases in cell density and λex, and a decrease in Pmem. These diffusivity measures increased with increases in nuclear volume and VFex. The diffusion heterogeneity measures (σgamma of the gamma distribution model and Kapp of the diffusional kurtosis model) increased with increases in cell density or nuclear volume at the low Pmem, and a decrease in Pmem. Increased σgamma was also associated with an increase in VFex. CONCLUSION: Among simulated microstructural changes, only increases in cell density at low Pmem or decreases in Pmem corresponded to both the decreased diffusivity and increased diffusion heterogeneity measures. The results suggest that increases in cell density at low Pmem or decreases in Pmem may be associated with the diffusion changes observed in high-grade gliomas.

Correlation between spinal cord diffusion tensor imaging and postural response latencies in persons with multiple sclerosis: A pilot study.

PURPOSE: Longer latency of postural response in multiple sclerosis (MS) may be linked to imbalance and increased likelihood of falls. It may be caused by the compromised microstructural integrity in the spinal cord, as evidenced by slowed somatosensory conduction in the spinal cord. Thus, the purpose of this study is to investigate the correlation between latency of postural responses and microstructural integrity of the cervical spinal cord, the region particularly related to the disease severity in MS, using diffusion tensor imaging (DTI) metrics. METHODS: Seventeen persons with MS with mild-to-moderate disease severity were enrolled in this study. Postural response latencies of each patient were measured using electromyography of the tibialis anterior muscle (TA) and gastrocnemius muscle (GN) in response to surface perturbations. Cervical spinal cord DTI images were obtained from each patient. DTI mean, radial, axial diffusivity, and fractional anisotropy (FA) were measured between segments C4 and C6. Correlations of DTI metrics with postural response latencies, expanded disability status scale (EDSS) scores, and 25-foot walk (T25FW) were assessed using the Spearman's rank correlation coefficient at α = 0.05. RESULTS: Lower FA was significantly correlated with longer latencies measured on right TA in response to forward postural perturbations (r = -0.51, p = .04). DTI metrics showed no significant correlations with EDSS scores (r = -0.06-0.09, p = .73-0.95) or T25FW (r = -0.1-0.14, p = .6-0.94). DTI metrics showed no significant differences between subjects with and without spinal cord lesions (p = .2-0.7). CONCLUSIONS: Our results showed a significant correlation between lower FA in the cervical spinal cord and longer latencies measured on right TA in response to forward postural perturbations in persons with MS, suggesting that impaired cervical spinal cord microstructure assessed by DTI may be associated with the delayed postural responses.

Early assessment of recurrent glioblastoma response to bevacizumab treatment by diffusional kurtosis imaging: a preliminary report.

PURPOSE: The purpose of this preliminary study is to apply diffusional kurtosis imaging to assess the early response of recurrent glioblastoma to bevacizumab treatment. METHODS: This prospective cohort study included 10 patients who had been diagnosed with recurrent glioblastoma and scheduled to receive bevacizumab treatment. Diffusional kurtosis images were obtained from all the patients 0-7 days before (pre-bevacizumab) and 28 days after (post-bevacizumab) initiating bevacizumab treatment. The mean, 10th, and 90th percentile values were derived from the histogram of diffusional kurtosis imaging metrics in enhancing and non-enhancing lesions, selected on post-contrast T1-weighted and fluid-attenuated inversion recovery images. Correlations of imaging measures with progression-free survival and overall survival were evaluated using Spearman's rank correlation coefficient. The significance level was set at P < 0.05. RESULTS: Higher pre-bevacizumab non-enhancing lesion volume was correlated with poor overall survival (r = -0.65, P = 0.049). Higher post-bevacizumab mean diffusivity and axial diffusivity (D∥, D∥10% and D∥90%) in non-enhancing lesions were correlated with poor progression-free survival (r = -0.73, -0.83, -0.71 and -0.85; P < 0.05). Lower post-bevacizumab axial kurtosis (K∥10%) in non-enhancing lesions was correlated with poor progression-free survival (r = 0.81, P = 0.008). CONCLUSIONS: This preliminary study demonstrates that diffusional kurtosis imaging metrics allow the detection of tissue changes 28 days after initiating bevacizumab treatment and that they may provide information about tumor progression.

Prospective frequency correction using outer volume suppression-localized navigator for MR spectroscopy and spectroscopic imaging.

PURPOSE: New frequency correction methods are required to achieve the accurate measurement of frequency drifts in MRS and MRSI. We present a prospective frequency correction method with outer volume suppression (OVS)-based localization and selective water excitation for effective frequency correction with better SNR improvement compared to other techniques. METHODS: An OVS-localized navigator was developed to prospectively correct frequency drifts during MRS and MRSI measurements. The performance of the navigator was tested on the human brain and a solution phantom for frequency drifts induced by head motion or gradient heating by a preceding DWI experiment at 3T. RESULTS: The OVS-localized navigator could accurately track motion-induced frequency drifts with an RMS error of 0.5 Hz. The SNR of MRS signals was not affected by use of the OVS-localized navigator when compared with and without the navigator (P > 0.05). The frequency drifts induced by DWI experiments were 5.1 ± 0.3 Hz/min during MRSI measurements on humans, resulting in increased spectral linewidth, significant bias in metabolite concentrations, and significantly increased Cramér-Rao lower bounds (P < 0.05). After prospective frequency corrections, the quality of MRSI was recovered to the level of those without any DWI-induced frequency drifts, judged by the spectral linewidth, metabolite concentrations, and Cramér-Rao lower bounds. CONCLUSION: The OVS-localized navigator demonstrated effective prospective frequency corrections for large frequency drifts (5 Hz/min) without introducing any saturation-induced SNR loss. These benefits can be particularly beneficial for the acquisition of MRS signals with long T1 and/or short TR, and spectral editing.

Human brain asymmetry in microstructural connectivity demonstrated by diffusional kurtosis imaging.

Structural asymmetry of whole brain white matter (WM) pathways, i.e., the connectome, has been demonstrated using fiber tractography based on diffusion tensor imaging (DTI). However, DTI-based tractography fails to resolve axonal fiber bundles that intersect within an imaging voxel, and therefore may not fully characterize the extent of asymmetry. The goal of this study was to assess structural asymmetry with tractography based on diffusional kurtosis imaging (DKI), which improves upon DTI-based tractography by delineating intravoxel crossing fibers. DKI images were obtained from 42 healthy subjects. By using automatic segmentation, gray matter (GM) was parcellated into anatomically defined regions of interest (ROIs). WM pathways were reconstructed with both DKI- and DTI-based tractography. The connectivity between the ROIs was quantified with the streamlines connecting the ROIs. The asymmetry index (AI) was utilized to quantify hemispheric differences in the connectivity of cortical ROIs and of links interconnecting cortical ROIs. Our results demonstrated that leftward asymmetrical ROIs and links were observed in frontal, parietal, temporal lobes, and insula. Rightward asymmetrical ROI and links were observed in superior frontal lobe, cingulate cortex, fusiform, putamen, and medial temporal lobe. Interestingly, these observed structural asymmetries were incompletely identified with DTI-based tractography. These results suggest that DKI-based tractography can improve the identification of asymmetrical connectivity patterns, thereby serving as an additional tool in the evaluation of the structural bases of functional lateralization.

Microstructural integrity of early- versus late-myelinating white matter tracts in medial temporal lobe epilepsy.

PURPOSE: Patients with medial temporal lobe epilepsy (MTLE) exhibit structural brain damage involving gray matter (GM) and white matter (WM). The mechanisms underlying tissue loss in MTLE are unclear and may be associated with a combination of seizure excitotoxicity and WM vulnerability. The goal of this study was to investigate whether late-myelinating WM tracts are more vulnerable to injury in MTLE compared with early myelinating tracts. METHODS: Diffusional kurtosis imaging scans were obtained from 25 patients with MTLE and from 36 matched healthy controls. Diffusion measures from regions of interest (ROIs) for both late- and early myelinating WM tracts were analyzed. Regional Z-scores were computed with respect to normal controls to compare WM in early myelinating tracts versus late-myelinating tracts. KEY FINDINGS: We observed that late-myelinating tracts exhibited a larger decrease in mean, axial, and radial kurtosis compared with early myelinating tracts. We also observed that the change in radial kurtosis was more pronounced in late-myelinating tracts ipsilateral to the side of seizure onset. SIGNIFICANCE: These results suggest a developmentally based preferential susceptibility of late-myelinating WM tracts to damage in MTLE. Brain injury in epilepsy may be due to the pathologic effects of seizures in combination with regional WM vulnerability.

Sensitivities of statistical distribution model and diffusion kurtosis model in varying microstructural environments: a Monte Carlo study.

The aim of this study was to investigate the microstructural sensitivity of the statistical distribution and diffusion kurtosis (DKI) models of non-monoexponential signal attenuation in the brain using diffusion-weighted MRI (DWI). We first developed a simulation of 2-D water diffusion inside simulated tissue consisting of semi-permeable cells and a variable cell size. We simulated a DWI acquisition of the signal in a volume using a pulsed gradient spin echo (PGSE) pulse sequence, and fitted the models to the simulated DWI signals using b-values up to 2500 s/mm(2). For comparison, we calculated the apparent diffusion coefficient (ADC) of the monoexponential model (b-value=1000 s/mm(2)). In separate experiments, we varied the cell size (5-10-15 µm), cell volume fraction (0.50-0.65-0.80), and membrane permeability (0.001-0.01-0.1mm/s) to study how the fitted parameters tracked simulated microstructural changes. The ADC was sensitive to all the simulated microstructural changes except the decrease in membrane permeability. The ADC increased with larger cell size, smaller cell volume fraction, and larger membrane permeability. The σstat of the statistical distribution model increased exclusively with a decrease in cell volume fraction. The Kapp of the DKI model was exclusively increased with decreased cell size and decreased with increasing membrane permeability. These results suggest that the non-monoexponential models of water diffusion have different, specific microstructural sensitivity, and a combination of the models may give insights into the microstructural underpinning of tissue pathology.

Turboprop+: enhanced Turboprop diffusion-weighted imaging with a new phase correction.

Faster periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) diffusion-weighted imaging acquisitions, such as Turboprop and X-prop, remain subject to phase errors inherent to a gradient echo readout, which ultimately limits the applied turbo factor (number of gradient echoes between each pair of radiofrequency refocusing pulses) and, thus, scan time reductions. This study introduces a new phase correction to Turboprop, called Turboprop+. This technique employs calibration blades, which generate 2-D phase error maps and are rotated in accordance with the data blades, to correct phase errors arising from off-resonance and system imperfections. The results demonstrate that with a small increase in scan time for collecting calibration blades, Turboprop+ had a superior immunity to the off-resonance-related artifacts when compared to standard Turboprop and recently proposed X-prop with the high turbo factor (turbo factor = 7). Thus, low specific absorption rate and short scan time can be achieved in Turboprop+ using a high turbo factor, whereas off-resonance related artifacts are minimized.

X-PROP: a fast and robust diffusion-weighted propeller technique.

Diffusion-weighted imaging (DWI) has shown great benefits in clinical MR exams. However, current DWI techniques have shortcomings of sensitivity to distortion or long scan times or combinations of the two. Diffusion-weighted echo-planar imaging (EPI) is fast but suffers from severe geometric distortion. Periodically rotated overlapping parallel lines with enhanced reconstruction diffusion-weighted imaging (PROPELLER DWI) is free of geometric distortion, but the scan time is usually long and imposes high Specific Absorption Rate (SAR) especially at high fields. TurboPROP was proposed to accelerate the scan by combining signal from gradient echoes, but the off-resonance artifacts from gradient echoes can still degrade the image quality. In this study, a new method called X-PROP is presented. Similar to TurboPROP, it uses gradient echoes to reduce the scan time. By separating the gradient and spin echoes into individual blades and removing the off-resonance phase, the off-resonance artifacts in X-PROP are minimized. Special reconstruction processes are applied on these blades to correct for the motion artifacts. In vivo results show its advantages over EPI, PROPELLER DWI, and TurboPROP techniques.