3D Echo-planar Spectroscopic Imaging Research Articles

Replicability of proton MR spectroscopic imaging findings in mild traumatic brain injury: Implications for clinical applications

PurposeProton magnetic resonance spectroscopy (1H MRS) offers biomarkers of metabolic damage after mild traumatic brain injury (mTBI), but a lack of replicability studies hampers clinical translation. In a conceptual replication study design, the results reported in four previous publications were used as the hypotheses (H1-H7), specifically: abnormalities in patients are diffuse (H1), confined to white matter (WM) (H2), comprise low N-acetyl-aspartate (NAA) levels and normal choline (Cho), creatine (Cr) and myo-inositol (mI) (H3), and correlate with clinical outcome (H4); additionally, a lack of findings in regional subcortical WM (H5) and deep gray matter (GM) structures (H6), except for higher mI in patients’ putamen (H7). Methods26 mTBI patients (20 female, age 36.5 ± 12.5 [mean ± standard deviation] years), within two months from injury and 21 age-, sex-, and education-matched healthy controls were scanned at 3 Tesla with 3D echo-planar spectroscopic imaging. To test H1-H3, global analysis using linear regression was used to obtain metabolite levels of GM and WM in each brain lobe. For H4, patients were stratified into non-recovered and recovered subgroups using the Glasgow Outcome Scale Extended. To test H5-H7, regional analysis using spectral averaging estimated metabolite levels in four GM and six WM structures segmented from T1-weighted MRI. The Mann-Whitney U test and weighted least squares analysis of covariance were used to examine mean group differences in metabolite levels between all patients and all controls (H1-H3, H5-H7), and between recovered and non-recovered patients and their respectively matched controls (H4). Replicability was defined as the support or failure to support the null hypotheses in accordance with the content of H1-H7, and was further evaluated using percent differences, coefficients of variation, and effect size (Cohen’s d). ResultsPatients’ occipital lobe WM Cho and Cr levels were 6.0% and 4.6% higher than controls’, respectively (Cho, d = 0.37, p = 0.04; Cr, d = 0.63, p = 0.03). The same findings, i.e., higher patients’ occipital lobe WM Cho and Cr (both p = 0.01), but with larger percent differences (Cho, 8.6%; Cr, 6.3%) and effect sizes (Cho, d = 0.52; Cr, d = 0.88) were found in the comparison of non-recovered patients to their matched controls. For the lobar WM Cho and Cr comparisons without statistical significance (frontal, parietal, temporal), unidirectional effect sizes were observed (Cho, d = 0.07 – 0.37; Cr, d = 0.27 – 0.63). No differences were found in any metabolite in any lobe in the comparison between recovered patients and their matched controls. In the regional analyses, no differences in metabolite levels were found in any GM or WM region, but all WM regions (posterior, frontal, corona radiata, and the genu, body, and splenium of the corpus callosum) exhibited unidirectional effect sizes for Cho and Cr (Cho, d = 0.03 – 0.34; Cr, d = 0.16 – 0.51). ConclusionsWe replicated findings of diffuse WM injury, which correlated with clinical outcome (supporting H1-H2, H4). These findings, however, were among the glial markers Cho and Cr, not the neuronal marker NAA (not supporting H3). No differences were found in regional GM and WM metabolite levels (supporting H5-H6), nor in putaminal mI (not supporting H7). Unidirectional effect sizes of higher patients’ Cho and Cr within all WM analyses suggest widespread injury, and are in line with the conclusion from the previous publications, i.e., that detection of WM injury may be more dependent upon sensitivity of the 1H MRS technique than on the selection of specific regions. The findings lend further support to the corollary that clinic-ready 1H MRS biomarkers for mTBI may best be achieved by using high signal-to-noise-ratio single-voxels placed anywhere within WM. The biochemical signature of the injury, however, may differ and therefore absolute levels, rather than ratios may be preferred. Future replication efforts should further test the generalizability of these findings.

Combining sodium MRI, proton MR spectroscopic imaging, and intracerebral EEG in epilepsy.

Whole brain ionic and metabolic imaging has potential as a powerful tool for the characterization of brain diseases. We combined sodium MRI (23 Na MRI) and 1 H-MR Spectroscopic Imaging (1 H-MRSI), assessing changes within epileptogenic networks in comparison with electrophysiologically normal networks as defined by stereotactic EEG (SEEG) recordings analysis. We applied a multi-echo density adapted 3D projection reconstruction pulse sequence at 7T (23 Na-MRI) and a 3D echo-planar spectroscopic imaging sequence at 3T (1 H-MRSI) in 19 patients suffering from drug-resistant focal epilepsy who underwent presurgical SEEG. We investigated 23 Na MRI parameters including total sodium concentration (TSC) and the sodium signal fraction associated with the short component of T2 * decay (f), alongside the level of metabolites N-acetyl aspartate (NAA), choline compounds (Cho), and total creatine (tCr). All measures were extracted from spherical regions of interest (ROIs) centered between two adjacent SEEG electrode contacts and z-scored against the same ROI in controls. Group comparison showed a significant increase in f only in the epileptogenic zone (EZ) compared to controls and compared to patients' propagation zone (PZ) and non-involved zone (NIZ). TSC was significantly increased in all patients' regions compared to controls. Conversely, NAA levels were significantly lower in patients compared to controls, and lower in the EZ compared to PZ and NIZ. Multiple regression analyzing the relationship between sodium and metabolites levels revealed significant relations in PZ and in NIZ but not in EZ. Our results are in agreement with the energetic failure hypothesis in epileptic regions associated with widespread tissue reorganization.

Method for fast lipid reconstruction and removal processing in 1 H MRSI of the brain.

To develop a new rapid spatial filtering method for lipid removal, fast lipid reconstruction and removal processing (FLIP), which selectively isolates and removes interfering lipid signals from outside the brain in a full-FOV 2D MRSI and whole-brain 3D echo planar spectroscopic imaging (EPSI). FLIP uses regularized least-squares regression based on spatial prior information from MRI to selectively remove lipid signals originating from the scalp and measure the brain metabolite signals with minimum cross contamination. FLIP is a noniterative approach, thus allowing a rapid processing speed, and uses only spatial information without any spectral priors. The performance of FLIP was compared with the Papoulis-Gerchberg algorithm (PGA), Hankel singular value decomposition (HSVD), and fast image reconstruction with L2 regularization (L2). FLIP in both 2D and 3D MRSI resulted in consistent metabolite quantification in a greater number of voxels with less concentration variation than other algorithms, demonstrating effective and robust lipid-removal performance. The percentage of voxels that met quality criteria with FLIP, PGA, HSVD, and L2 processing were 90%, 57%, 29%, and 42% in 2D MRSI, and 80%, 75%, 76%, and 74% in 3D EPSI, respectively. The quantification results of full-FOV MRSI using FLIP were comparable to those of volume-localized MRSI, while allowing significantly increased spatial coverage. FLIP performed the fastest in 2D MRSI. FLIP is a new lipid-removal algorithm that promises fast and effective lipid removal with improved volume coverage in MRSI.

Sensitivity to myelin using model-free analysis of the water resonance line-shape in postmortem mouse brain.

Dysmyelinating diseases are characterized by abnormal myelin formation and function. Such microstructural abnormalities in myelin have been demonstrated to produce measurable effects on the MR signal. This work examines these effects on measurements of voxel-wise, high-resolution water spectra acquired using a 3D echo-planar spectroscopic imaging (EPSI) pulse sequence from both postmortem fixed control mouse brains and a dysmyelination mouse brain model. Perfusion fixed, resected control (n = 5) and shiverer (n = 4) mouse brains were imaged using 3D-EPSI with 100 µm isotropic resolution. The free induction decay (FID) was sampled every 2.74 ms over 192 echoes, for a total sampling duration of 526.08 ms. Voxel-wise FIDs were Fourier transformed to produce water spectra with 1.9 Hz resolution. Spectral asymmetry was computed and compared between the two tissue types. The water resonance is more asymmetrically broadened in the white matter of control mouse brain compared with dysmyelinated white matter. In control brain, this is modulated by and consistent with previously reported orientationally dependent effects of white matter relative to B0 . Similar sensitivity to orientation is observed in dysmyelinated white matter as well; however, the magnitude of the resonance asymmetry is much lower across all directions. Results demonstrate that components of the spectra are specifically differentially affected by myelin concentration. This suggests that water proton spectra may be sensitive to the presence of myelin, and as such, could serve as a MRI-based biomarker of dysmyelinating disease, free of mathematical models.

Hyperpolarized 13 C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco.

Based on the expanding set of applications for hyperpolarized carbon-13 (HP-13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP-13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP-13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information.

The effects of variations in tissue microstructure from postmortem rat brain on the asymmetry of the water proton resonance.

This work was performed to investigate the effects of tissue microstructure from postmortem rat brain on the shape of the water proton spectrum. Perfusion-fixed, resected rat brains (N = 4) were imaged at 9.4T. 3D DTI and 3D echo-planar spectroscopic imaging (EPSI) data were acquired with 150 μm isotropic resolution. DTI data were acquired over 60 directions with b = 3000 s/mm2 . Water spectra were produced from EPSI data acquired over 128 echoes, with 2.9 Hz spectral resolution. A voxel-wise metric reflecting spectral asymmetry about the peak of the resonance was computed and compared with orientation estimates from DTI data by fitting data with the susceptibility anisotropy model. Asymmetric broadening of the water resonance was computed for mixed populations of grey and/or white matter as determined by thresholding the fractional anisotropy. Asymmetry was shown to be differentially affected by tract orientation relative to B0 in high FA voxels, whereas low FA voxels exhibited little sensitivity. Anatomic structures in the hippocampus were also found to produce distinct changes in the water resonance. Present results demonstrate that structural variations in tissue architecture cause characteristic, reproducible changes in the water resonance shape. This suggests that water spectra are sensitive to cytoarchitectural variations in brain tissue.

Abstract CT068: Tumor treating fields in patients with glioblastomas: Evaluation of treatment response using advanced mr imaging techniques

Abstract Introduction: Tumor treating fields (TTFields) is a new modality for the treatment of patients with newly diagnosed and recurrent glioblastomas (GBMs). TTFields system delivers low intensity, intermediate frequency alternating electric field directly to brain causing neoplastic cell death with minimal effect on the normal dividing cells. The purpose of present investigator sponsored trial was to evaluate the effects of TTFields in GBM patients using diffusion tensor imaging (DTI), perfusion weighted imaging (PWI) and 3D-echoplanar spectroscopic imaging (EPSI). Methods: Two patients with newly diagnosed GBM and six patients with recurrent GBMs previously treated with standard of care maximal safe resection and chemo-radiation therapy received TTFields. Patients underwent baseline (prior to TTFields) and two follow-up (one and two months post initiation of TTFields) MR imaging on a 3T MR system. DTI data were acquired using 30 directions with a single-shot spin-echo EPI sequence. After motion and eddy current correction of raw DTI data, parametric maps [mean diffusivity (MD), fractional anisotropy (FA)] were generated using in-house developed algorithm. For PWI, T2* weighted gradient-echo EPI sequence was acquired with a temporal resolution of 2.1s. Leakage corrected cerebral blood volume (CBV) maps were constructed. 3D-EPSI was acquired using a spin-echo based sequence. EPSI data were processed using metabolic imaging and data analysis system (MIDAS) package. DTI (MD, FA), EPSI [choline (Cho)/creatine(Cr)], CBV maps and FLAIR images were co-registered to post-contrast T1-weighted images and a semi-automated algorithm was used to segment the contrast-enhancing region of neoplasms. Median values of MD, FA, relative CBV (rCBV) and Cho/Cr were computed at each time point. The 90th percentile rCBV (rCBVmax) values were also measured. Percent changes of each parameter between baseline and follow-up time points were evaluated. Results and Discussion: In general, there was an increasing trend in MD (~3%) and steadily decline trend in FA (~8%) at the 2 month follow-up relative to baseline. Additionally, from baseline to post- TTFields, reductions in Cho/Cr and rCBVmax were also observed from most of the patients. Clinically, all these patients were stable at 2 month follow-up. The inhibited cellular growth may account for large increase in MD and decrease in FA and Cho/Cr as observed in the current study. Reducing trends in rCBVmax at the follow-up may indicate anti- angiogenetic effects of TTFields and tissue perfusion within the tumor bed after the therapy. Conclusion: Our preliminary data suggest that advanced MR imaging may be useful in evaluating treatment response to TTFields in patients with GBMs. Inclusion of more patients is warranted to validate our findings. Acknowledgement: Support of NovoTTF-100A system (Novocure Ltd., Haifa, Israel) is gratefully acknowledged. Citation Format: SANJEEV CHAWLA, Sumei Wang, Gaurav Verma, Aaron Skolnik, Lauren Karpf, Lisa Desiderio, Steven Brem, Katherine Peters, Harish Poptani, Suyash Mohan. Tumor treating fields in patients with glioblastomas: Evaluation of treatment response using advanced mr imaging techniques [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT068. doi:10.1158/1538-7445.AM2017-CT068

The Need and Initial Practice of Parallel Imaging and Compressed Sensing in Hyperpolarized 13C MRI in vivo.

The Need and Initial Practice of Parallel Imaging and Compressed Sensing in Hyperpolarized 13C MRI in vivo.

Whole-brain quantitative mapping of metabolites using short echo three-dimensional proton MRSI.

To improve the extent over which whole brain quantitative three-dimensional (3D) magnetic resonance spectroscopic imaging (MRSI) maps can be obtained and be used to explore brain metabolism in a population of healthy volunteers. Two short echo time (20 ms) acquisitions of 3D echo planar spectroscopic imaging at two orientations, one in the anterior commissure-posterior commissure (AC-PC) plane and the second tilted in the AC-PC +15° plane were obtained at 3 Tesla in a group of 10 healthy volunteers. B1 (+) , B1 (-) , and B0 correction procedures and normalization of metabolite signals with quantitative water proton density measurements were performed. A combination of the two spatially normalized 3D-MRSI, using a weighted mean based on the pixel wise standard deviation metabolic maps of each orientation obtained from the whole group, provided metabolite maps for each subject allowing regional metabolic profiles of all parcels of the automated anatomical labeling (AAL) atlas to be obtained. The combined metabolite maps derived from the two acquisitions reduced the regional intersubject variance. The numbers of AAL regions showing N-acetyl aspartate (NAA) SD/Mean ratios lower than 30% increased from 17 in the AC-PC orientation and 41 in the AC-PC+15° orientation, to a value of 76 regions of 116 for the combined NAA maps. Quantitatively, regional differences in absolute metabolite concentrations (mM) over the whole brain were depicted such as in the GM of frontal lobes (cNAA = 10.03 + 1.71; cCho = 1.78 ± 0.55; cCr = 7.29 ± 1.69; cmIns = 5.30 ± 2.67) and in cerebellum (cNAA = 5.28 ± 1.77; cCho = 1.60 ± 0.41; cCr = 6.95 ± 2.15; cmIns = 3.60 ± 0.74). A double-angulation acquisition enables improved metabolic characterization over a wide volume of the brain.

NI-15 * USE OF VOLUMETRIC MR SPECTROSCOPIC IMAGING AND 5-ALA FLUORESCENCE-GUIDED SURGERY FOR RESECTION OF GLIOBLASTOMA

RATIONALE: Glioblastoma (GBM) resection based on neuronavigation with contrast-enhanced MRI (CE-MRI) results in a high rate of local recurrence as infiltrating tumor cells extend beyond areas of contrast enhancement. Integrating metabolic maps from magnetic resonance spectroscopic imaging (MRSI) into neuronavigation may identify high-risk tumor infiltration zones outside of CE-MRI for surgery. Coupling MRSI with fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) may provide a means to further enhance the degree of tumor resection. METHODS: In a new Phase II trial for new and recurrent GBM patients, 3D-echo planar spectroscopic imaging was performed and processed to give full-brain metabolite volumes for import into a neuronavigation station. Patients were administered 5-ALA orally 3-5 h before surgery. To minimize error due to shift, needle biopsies were collected from tumor regions with elevated choline/NAA values within T1CE and/or T2/FLAIR hyperintense regions before tumor resection. Fluorescence intensity of fresh tissue was quantified ex vivo using a hand-held spectroscopic device. Samples were then fixed/stained with H&E and analyzed for tumor cell density and tissue infiltration using automated image analysis techniques. Quantitative tumor segmentation was used to evaluate extent of tumor resection. RESULTS: Choline/NAA values show a positive linear trend with the number of tumor nuclei per high power field and the degree of tumor infiltration. Real-time intraoperative tumor fluorescence was also confirmed ex vivo and shows a similar positive linear trend with choline/NAA ratios. CONCLUSIONS: The linear trend that Cho/NAA values exhibit with histopathology and quantitative intraoperative fluorescence of tumor tissue outside of CE-MRI regions supports its use for identifying regions of tumor infiltration. This is the first time that 5-ALA induced tumor fluorescence has been shown to correlate with MRSI-derived metabolic markers in GBM tumors. We believe the continued combination of MRSI-neuronavigation with 5-ALA FGS in this trial will result in more complete GBM resections.

Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis

MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE.

Spectral phase‐corrected GRAPPA reconstruction of three‐dimensional echo‐planar spectroscopic imaging (3D‐EPSI)

MR spectroscopic (MRS) images from a large volume of brain can be obtained using a 3D echo-planar spectroscopic imaging (3D-EPSI) sequence. However, routine applications of 3D-EPSI are still limited by a long scan time. In this communication, a new approach termed "spectral phase-corrected generalized autocalibrating partially parallel acquisitions" (SPC-GRAPPA) is introduced for the reconstruction of 3D-EPSI data to accelerate data acquisition while preserving the accuracy of quantitation of brain metabolites. In SPC-GRAPPA, voxel-by-voxel spectral phase alignment between metabolite 3D-EPSI from individual coil elements is performed in the frequency domain, utilizing the whole spectrum from interleaved water reference 3D-EPSI for robust estimation of the zero-order phase correction. The performance of SPC-GRAPPA was compared with that of fully encoded 3D-EPSI and conventional GRAPPA. Analysis of whole-brain 3D-EPSI data reconstructed by SPC-GRAPPA demonstrates that SPC-GRAPPA with an acceleration factor of 1.5 yields results very similar to those obtained by fully encoded 3D-EPSI, and is more accurate than conventional GRAPPA.

Correction of local B0 shifts in 3D EPSI of the human brain at 4 T

High-spatial-resolution acquisition (HR) was previously proposed for 3D echo-planar spectroscopic imaging (EPSI) in combination with a high-spatial-resolution water reference EPSI data set to minimize inhomogeneous spectral line broadening, allowing for local frequency shift (B(0) shift) correction in human brain metabolite maps at 1.5 T (Ebel A et al., Magn. Reson. Imaging 21:113-120, 2003). At a higher magnetic field strength, B(0), increased field inhomogeneities typically lead to increased line broadening. Additionally, increased susceptibility variations render shimming of the main magnetic field over the whole head more difficult. This study addressed the question whether local B(0)-shift correction still helps limit line broadening in whole-brain 3D EPSI at higher magnetic fields. The combination of HR and local B(0)-shift correction to limit line broadening was evaluated at 4 T. Similar to the results at 1.5 T, the approach provided a high yield of voxels with good spectral quality for 3D EPSI, resulting in improved brain coverage.

Achieving sufficient spectral bandwidth for volumetric 1H echo‐planar spectroscopic imaging at 4 Tesla

Complete coverage of the in vivo proton metabolite spectrum, including downfield resonances, requires a spectral bandwidth of approximately 9 ppm. Spectral bandwidth of in vivo echo-planar spectroscopic imaging (EPSI) is primarily limited by gradient strength of the oscillating readout gradient, gradient slew rate, and limits on peripheral nerve stimulation for human subjects. Furthermore, conventional EPSI reconstruction, which utilizes even and odd readout echoes separately, makes use of only half the spectral bandwidth. In order to regain full spectral bandwidth in EPSI, it has previously been suggested to apply an interlaced Fourier transform (iFT), which uses even and odd echoes simultaneously. However, this method has not been thoroughly analyzed regarding its usefulness for in vivo 3D EPSI. In this Note, limitations of the iFT method are discussed and an alternative, cyclic spectral unwrapping, is proposed, which is based on prior knowledge of typical in vivo spectral patterns.