Echo-planar Spectroscopic Imaging Research Articles

NNFit: A Self-Supervised Deep Learning Method for Accelerated Quantification of High- Resolution Short Echo Time MR Spectroscopy Datasets.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To develop and evaluate the performance of NNFit, a self-supervised deep-learning method for quantification of high-resolution short echo-time (TE) echo-planar spectroscopic imaging (EPSI) datasets, with the goal of addressing the computational bottleneck of conventional spectral quantification methods in the clinical workflow. Materials and Methods This retrospective study included 89 short-TE whole-brain EPSI/GRAPPA scans from clinical trials for glioblastoma (Trial 1, May 2014-October 2018) and major-depressive-disorder (Trial 2, 2022- 2023). The training dataset included 685k spectra from 20 participants (60 scans) in Trial 1. The testing-dataset included 115k spectra from 5 participants (13 scans) in Trial 1 and 145k spectra from 7 participants (16 scans) in Trial 2. A comparative analysis was performed between NNFit and a widely used parametric-modeling spectral quantitation method (FITT). Metabolite maps generated by each method were compared using the structural- similarity-index-measure (SSIM) and linear-correlation-coefficient (R2). Radiation treatment volumes for glioblastoma based on the metabolite maps were compared with the Dice-coefficient and a two-tailed t test. Results Average SSIM and R2 scores for Trial 1 test set data were 0.91/0.90 (choline), 0.93/0.93 (creatine), 0.93/0.93 (n-acetylaspartate), 0.80/0.72 (myo-inositol), and 0.59/0.47 (glutamate + glutamine). Average scores for Trial 2 test set data were 0.95/0.95, 0.98/0.97, 0.98/0.98, 0.92/0.92, and 0.79/0.81 respectively. The treatment volumes had average Dice coefficient of 0.92. NNFit's average processing time was 90.1 seconds, whereas FITT took 52.9 minutes on average. Conclusion This study demonstrates that a deep learning approach to spectral quantitation offers comparable performance to conventional quantification methods for EPSI data, but with faster processing at short-TE. ©RSNA, 2025.

Assessment of spectral ghost artifacts in echo-planar spectroscopic micro-imaging with flyback readout

In this work, echo-planar spectroscopic imaging (EPSI) with flyback readout gradient-echo train was implemented in a preclinical MR scanner. The aim of this study is to visualize and quantify the ghost spectral lines produced by two, three and four interleaved echo trains with different amplitudes of the readout gradients, and to investigate the feasibility of the flyback data acquisition in micro-imaging of small animals. Applied multi-slice EPSI sequence utilizes asymmetric gradient-echo train that combines the shortest possible rewind gradients with readout gradients. It simplifies data processing because all echoes are acquired with the same polarity of the readout gradient. The approach with four interleaved gradient-echo trains and with four echoes in each train provides broad spectral bandwidth in combination with narrow receiver bandwidth and a good water-fat signal separation. It improves signal-to-noise ratio without the undesired consequence of water-fat shift artifacts that are eliminated during data processing. Position, number, and intensity of the ghost spectral lines can be controlled by the suitable choice of spectral bandwidth, number of echo train interleaves, and the number of echoes in each interleave. This study demonstrates that high-spatial resolution EPSI with interleaved flyback readout gradient-echo trains is feasible on standard preclinical scanners.

Three-dimensional radial echo-planar spectroscopic imaging for hyperpolarized 13C MRSI in vivo.

To demonstrate the feasibility of 3D echo-planar spectroscopic imaging (EPSI) technique with rapid volumetric radial k-space sampling for hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) in vivo. A radial EPSI (rEPSI) was implemented on a 3 T clinical PET/MR system. To enable volumetric coverage, the sinusoidal shaped readout gradients per k-t-spoke were rotated along the three spatial dimensions in a golden-angle like manner. A distance-weighted, density-compensated gridding reconstruction was used, also in cases with undersampling of spokes in k-space. Measurements without and with HP 13C-labeled substances were performed in phantoms and rats using a double-resonant 13C/1H volume resonator with 72 mm inner diameter. Phantom measurements demonstrated the feasibility of the implemented rEPSI sequence, as well as the robustness to undersampling in k-space up to a factor of 5 without advanced reconstruction techniques. Applied to measurements with HP [1-13C]pyruvate in a tumor-bearing rat, we obtained well-resolved MRSI datasets with a large matrix size of 123 voxels covering the whole imaging FOV of (180 mm)3 within 6.3 s, enabling to observe metabolism in dynamic acquisitions. After further optimization, the proposed rEPSI method may be useful in applications of HP 13C-tracers where unknown or varying metabolite resonances are expected, and the acquisition of dynamic, volumetric MRSI datasets with an adequate temporal resolution is a challenge.

Single-shot diffusion trace spectroscopic imaging using radial echo planar trajectories.

Demonstrate the feasibility and evaluate the performance of single-shot diffusion trace-weighted radial echo planar spectroscopic imaging (Trace DW-REPSI) for quantifying the trace ADC in phantom and in vivo using a 3T clinical scanner. Trace DW-REPSI datasets were acquired in 10 phantom and 10 healthy volunteers, with a maximum b-value of 1601 s/mm2 and diffusion time of 10.75 ms. The self-navigation properties of radial acquisitions were used for corrections of shot-to-shot phase and frequency shift fluctuations of the raw data. In vivo trace ADCs of total NAA (tNAA), total creatine (tCr), and total choline (tCho) extrapolated to pure gray and white matter fractions were compared, as well as trace ADCs estimated in voxels within white or gray matter-dominant regions. Trace ADCs in phantom show excellent agreement with reported values, and in vivo ADCs agree well with the expected differences between gray and white matter. For tNAA, tCr, and tCho, the trace ADCs extrapolated to pure gray and white matter ranged from 0.18-0.27 and 0.26-0.38 μm2/ms, respectively. In sets of gray and white matter-dominant voxels, the values ranged from 0.21 to 0.27 and 0.24 to 0.31 μm2/ms, respectively. The overestimated trace ADCs from this sequence can be attributed to the short diffusion time. This study presents the first demonstration of the single-shot diffusion trace-weighted spectroscopic imaging sequence using radial echo planar trajectories. The Trace DW-REPSI sequence could provide an estimate of the trace ADC in a much shorter scan time compared to conventional approaches that require three separate measurements.

Spatially encoded pure-shift diffusion-ordered NMR spectroscopy yielded by chirp excitation

Spatially-encoded diffusion-ordered NMR spectroscopy (SPEN-DOSY) has emerged as a new time-efficient tool for the analysis of mixtures of small molecules in solution. Time efficiency is achieved using the concept of spatial parallelization of the effective gradient area, instead of the sequential incrementation used in conventional diffusion experiments. The data acquired with such sequences are then usually processed to extract diffusion coefficients, but cases when peak overlap in the 1H spectrum are difficult to address. Such limitation in conventional diffusion experiments is addressed via using the Pure Shift Yielded by CHirp Excitation (PSYCHE)-iDOSY sequence. Here we have adapted the PSYCHE-iDOSY sequence by using echo planar spectroscopic imaging (EPSI) to acquire SPEN-DOSY data. The pure shift mode of PSYCHE separates the overlapped components and a modified Stejskal-Tanner equation is used to extract the corresponding diffusion coefficient. The primary results obtained with the above-mentioned mixtures seem to open the possibility of separating complex mixtures in less time than PSYCHE-iDOSY.

A silent echo-planar spectroscopic imaging readout with high spectral bandwidth MRSI using an ultrasonic gradient axis.

We present a novel silent echo-planar spectroscopic imaging (EPSI) readout, which uses an ultrasonic gradient insert to accelerate MRSI while producing a high spectral bandwidth (20 kHz) and a low sound level. The ultrasonic gradient insert consisted of a single-axis (z-direction) plug-and-play gradient coil, powered by an audio amplifier, and produced 40 mT/m at 20 kHz. The silent EPSI readout was implemented in a phase-encoded MRSI acquisition. Here, the additional spatial encoding provided by this silent EPSI readout was used to reduce the number of phase-encoding steps. Spectroscopic acquisitions using phase-encoded MRSI, a conventional EPSI-readout, and the silent EPSI readout were performed on a phantom containing metabolites with resonance frequencies in the ppm range of brain metabolites (0-4 ppm). These acquisitions were used to determine sound levels, showcase the high spectral bandwidth of the silent EPSI readout, and determine the SNR efficiency and the scan efficiency. The silent EPSI readout featured a 19-dB lower sound level than a conventional EPSI readout while featuring a high spectral bandwidth of 20 kHz without spectral ghosting artifacts. Compared with phase-encoded MRSI, the silent EPSI readout provided a 4.5-fold reduction in scan time. In addition, the scan efficiency of the silent EPSI readout was higher (82.5% vs. 51.5%) than the conventional EPSI readout. We have for the first time demonstrated a silent spectroscopic imaging readout with a high spectral bandwidth and low sound level. This sound reduction provided by the silent readout is expected to have applications in sound-sensitive patient groups, whereas the high spectral bandwidth could benefit ultrahigh-field MR systems.

Beat phenomena of oscillating readouts.

To demonstrate slowly varying, erroneous magnetic field gradients for oscillating readouts due to the mechanically resonant behavior of gradient systems. Projections of a static phantom were acquired using a one-dimensional (1D) EPI sequence with varying EPI frequencies ranging from 1121 to 1580 Hz on clinical 3T systems (30 mT/m, 200 T/m/s). Phase due to static B0 inhomogeneities was eliminated by a complex division of two separate scans with different polarities of the EPI readout. The temporal evolution of phase was evaluated and related to the mechanical resonances of the gradient systems derived from the gradient modulation transfer function. Additionally, the impact of temporally varying mechanical resonance effects on EPI was evaluated using an echo-planar spectroscopic imaging sequence. A beat phenomenon resulting in a slowly varying phase was observed. Its temporal frequency was given by the difference between the EPI frequency and the mechanical resonance frequency of the activated gradient axis. The maximum erroneous, oscillating phase during phase encoding was ±0.5 rad for an EPI frequency of 1281 Hz. Echo-planar spectroscopic imaging images showed the resulting time-dependent stretching/compression of the FOV. Oscillating readouts such as those used in EPI can result in low-frequency, erroneous phase contributions, which are explained by the beat phenomenon. Therefore, EPI phase-correction approaches may need to include beat effects for accurate image reconstruction.

Deuterium echo-planar spectroscopic imaging (EPSI) in the human liver in vivo at 7 T.

To demonstrate the feasibility of deuterium echo-planar spectroscopic imaging (EPSI) to accelerate 3D deuterium metabolic imaging in the human liver at 7 T. A deuterium EPSI sequence, featuring a Hamming-weighted k-space acquisition pattern for the phase-encoding directions, was implemented. Three-dimensional deuterium EPSI and conventional MRSI were performed on a water/acetone phantom and in vivo in the human liver at natural abundance. Moreover, in vivo deuterium EPSI measurements were acquired after oral administration of deuterated glucose. The effect of acquisition time on SNR was evaluated by retrospectively reducing the number of averages. The SNR of natural abundance deuterated water signal in deuterium EPSI was 6.5% and 5.9% lower than that of MRSI in the phantom and in vivo experiments, respectively. In return, the acquisition time of in vivo EPSI data could be reduced retrospectively to 2 min, beyond the minimal acquisition time of conventional MRSI (of 20 min in this case), while still leaving sufficient SNR. Three-dimensional deuterium EPSI, after administration of deuterated glucose, enabled monitoring of hepatic glucose dynamics with full liver coverage, a spatial resolution of 20 mm isotropic, and a temporal resolution of 9 min 50 s, which could retrospectively be shortened to 2 min. In this work, we demonstrate the feasibility of accelerated 3D deuterium metabolic imaging of the human liver using deuterium EPSI. The acceleration obtained with EPSI can be used to increase temporal and/or spatial resolution, which will be valuable to study tissue metabolism of deuterated compounds over time.

Spectroscopic MRI-Guided Proton Therapy in Non-Enhancing Pediatric High-Grade Glioma.

Radiation therapy (RT) is a critical part of definitive therapy for pediatric high-grade glioma (pHGG). RT is designed to treat residual tumor defined on conventional MRI (cMRI), though pHGG lesions may be ill-characterized on standard imaging. Spectroscopic MRI (sMRI) measures endogenous metabolite concentrations in the brain, and Choline (Cho)/N-acetylaspartate (NAA) ratio is a highly sensitive biomarker for metabolically active tumor. We provide a preliminary report of our study introducing a novel treatment approach of whole brain sMRI-guided proton therapy for pHGG. An observational cohort (c1 = 10 patients) receives standard of care RT; a therapeutic cohort (c2 = 15 patients) receives sMRI-guided proton RT. All patients undergo cMRI and sMRI, a high-resolution 3D whole-brain echo-planar spectroscopic imaging (EPSI) sequence (interpolated resolution of 12 µL) prior to RT and at several follow-up timepoints integrated into diagnostic scans. Treatment volumes are defined by cMRI for c1 and by cMRI and Cho/NAA ≥ 2x for c2. A longitudinal imaging database is used to quantify changes in lesion and metabolite volumes. Four subjects have been enrolled (c1 = 1/c2 = 3) with sMRI imaging follow-up of 4-18 months. Preliminary data suggest sMRI improves identification of pHGG infiltration based on abnormal metabolic activity, and using proton therapy to target sMRI-defined high-risk regions is safe and feasible.

Simultaneous Mapping of Water Diffusion Coefficients and Metabolite Distributions of the Brain Using MR Spectroscopic Imaging without Water Suppression.

To simultaneously map water diffusion coefficients and metabolite distributions of the brain in magnetic resonance spectroscopic imaging (MRSI) experiments within a clinically feasible time. A diffusion-preparation module was introduced in water-unsuppressed MRSI acquisition sequence to generate diffusion weighting of the water signals. Fast spatiospectral encodings were achieved using echo-planar spectroscopic imaging readouts with blipped phase encodings for sparse sampling. Navigator signals were embedded in the data acquisition sequence, which were used for detection of data corrupted by physiological motion in the diffusion preparation period. In data processing, a novel model-based method was developed to effectively use sparse (k, t)-space spectroscopic signals for reconstruction of the spatial distributions of water diffusion coefficients and metabolite concentrations. Both phantom experiments and in vivo experiments were carried out to evaluate the feasibility and performance of the proposed method. In an 8-minute scan, diffusion weighted images and apparent diffusion coefficients map at 2.0×1.0×1.0 mm3 were obtained simultaneously with metabolite maps at 2.0×3.0×3.0 mm3 nominal resolution. We demonstrated the feasibility of using the unsuppressed water signals from MRSI experiments to map the water diffusion coefficients of brain tissues and proposed a novel method to achieve simultaneous mapping of water diffusion coefficients and metabolite distributions. The proposed method provides a unique imaging tool for simultaneous diffusion and metabolic imaging. This method is expected to be useful for various brain imaging applications.

Monitoring response to a clinically relevant IDH inhibitor in glioma-Hyperpolarized 13C magnetic resonance spectroscopy approaches.

Mutant isocitrate dehydrogenase (IDHmut) catalyzes 2-hydroxyglutarate (2HG) production and is considered a therapeutic target for IDHmut tumors. However, response is mostly associated with inhibition of tumor growth. Response assessment via anatomic imaging is therefore challenging. Our goal was to directly detect IDHmut inhibition using a new hyperpolarized (HP) 13C magnetic resonance spectroscopy-based approach to noninvasively assess α-ketoglutarate (αKG) metabolism to 2HG and glutamate. We studied IDHmut-expressing normal human astrocyte (NHAIDH1mut) cells and rats with BT257 tumors, and assessed response to the IDHmut inhibitor BAY-1436032 (n ≥ 4). We developed a new 13C Echo Planar Spectroscopic Imaging sequence with an optimized RF pulse to monitor the fate of HP [1-13C]αKG and [5-12C,1-13C]αKG with a 2.5 × 2.5 × 8 mm3 spatial resolution. Cell studies confirmed that BAY-1436032-treatment leads to a drop in HP 2HG and an increase in HP glutamate detectable with both HP substrates. Data using HP [5-12C,1-13C]αKG also demonstrated that its conversion to 2HG is detectable without the proximal 1.1% natural abundance [5-13C]αKG signal. In vivo studies showed that glutamate is produced in normal brains but no 2HG is detectable. In tumor-bearing rats, we detected the production of both 2HG and glutamate, and BAY-1436032-treatment led to a drop in 2HG and an increase in glutamate. Using HP [5-12C,1-13C]αKG we detected metabolism with an signal-to-noise ratio of 23 for 2HG and 17 for glutamate. Our findings point to the clinical potential of HP αKG, which recently received FDA investigational new drug approval for research, for noninvasive localized imaging of IDHmut status.

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.

Emerging metabolic imaging and spectroscopic methods to study neurodegenerative diseases

Proton magnetic resonance spectroscopy (1H-MRS) allows non-invasive assessment of the metabolic landscape of biological tissue. Despite demonstrating promising findings in clinical practice, single-voxel or single-slice two-dimensional 1H-MRS methods present a few challenges mainly related to limited spatial coverage and low spatial and spectral resolutions. In the recent past, the advent of more sophisticated metabolic imaging and spectroscopic sequences, such as three-dimensional echoplanar spectroscopic imaging (3D-EPSI), two-dimensional correlation spectroscopy (2D-COSY), and chemical exchange saturation technique (CEST) has revolutionized the field of metabolomics. For the metabolic characterization of diffused neurodegenerative diseases, whole brain coverage is essential for a comprehensive overview of the topography and understanding of the underlying pathophysiological processes. The 3D-EPSI sequence allows the acquisition of whole brain (volumetric) metabolite maps with high spatial resolution.1 These metabolite maps can be co-registered to anatomical images for facilitating the mapping of metabolite alterations from different brain regions in a single session, thus providing the true spatial extent of a global disease. The potential of 3D‐EPSI in characterizing several neurological and neurodegenerative disorders has been reported. On conventional one-dimensional 1H-MRS, spectral peaks due to methyl, methylene, and methine protons from N-acetyl aspartate, glutamate, glutamine, gamma-aminobutyric acid, and taurine extensively overlap in the spectral region of 2-4 ppm, often confounding the reliable detection and quantification of these metabolites. In contrast, 2D-COSY offers unambiguous identification of potentially overlapping resonances by dispersing the multiplet structure of scalar (J)-coupled spin systems into a second spectral dimension,2 especially at higher field strength3,4 and by exploiting the unlikely possibility that two metabolites would share identical chemical shifts in two-dimensions. Due to technical limitations and long acquisition time, 2D-COSY sequence has not been widely used to study neurodegenerative diseases. However, future modifications would benefit from implementing faster acquisition schemes and improved spectral fitting methods for data analysis. We believe that these new approaches could make the clinical applications of the 2D-COSY sequence faster, easier, and more versatile. CEST is a relatively novel metabolic imaging modality that allows the detection of specific exogenous and endogenous metabolites/molecules present at millimolar concentrations. Exchangeable solute protons present in chemical functional groups such as amide (-CONH), amine (-NH2) or hydroxyl (-OH) resonate at a frequency different from bulk water protons. These labile protons are selectively saturated using radiofrequency irradiation, which is subsequently transferred to the bulk water pool, leading to a decrease in the water signal intensity proportional to the concentration of solute molecules, number of labile protons and proton exchange rate.5 CEST offers more than two orders of magnitude higher sensitivity compared to 1H-MRS in detecting metabolites such as glutamate, creatine, myoinositol and mobile peptides.5 While amide proton transfer (APT) imaging has been investigated in various neurological disorders, other CEST imaging techniques such as glutamate-CEST, creatine-CEST have been performed only in pre-clinical or pilot clinical studies related to neurodegenerative diseases. We believe that these newer developments in metabolic imaging techniques will have a significant impact in reshaping our understanding of biochemical profiles of various neurodegenerative diseases. However, standardization and harmonization of acquisition parameters are required for fast-tracking the implementation of these metabolic techniques into routine clinical workflow.

TMET-12. HYPERPOLARIZED Δ- [1-13C] GLUCONOLACTONE IMAGING VISUALIZES TERT-ASSOCIATED CHANGES IN DYNAMIC PENTOSE PHOSPHATE PATHWAY METABOLISM IN GLIOBLASTOMA

Abstract BACKGROUND TERT promoter mutations are a hallmark of glioblastoma (GBM). We recently reported that the expression of TERT and its upstream transcriptional factor, GABPB1, are strongly correlated with redox in GBM with TERT promoter mutations. However, further imaging biomarkers which visualize redox-associated metabolism and TERT expression are needed. Here we demonstrate that 13C magnetic resonance spectroscopy (MRS) of hyperpolarized δ-[1-13C] gluconolactone metabolism is a useful imaging tool to visualize changes in dynamic pentose phosphate pathway (PPP) metabolism that reflect TERT-associated changes in redox in GBM. METHODS U251 human GBM cells stably expressing shRNA targeting TERT or GABPB1 were compared to controls. Doxycyclin-inducible shTERT or shGABPB1 U251 cells were also examined. For in vivo studies, cells were injected into immunodeficient rat brains and tumors confirmed by T2-weighted MRI. δ-[1-13C] gluconolactone was polarized using a Hypersense DNP polarizer and injected into live cells or tumor-bearing rats. For cells 13C-MRS was acquired using a 500MHz Agilent spectrometer and analyzed using Mnova and Matlab software. For in vivo13C-MRS studies, spectra were acquired using a 3T Bruker scanner and a spectral spatial echo-planar spectroscopic imaging sequence. Spectral signal to noise was improved using Tensor denoising. Spectra were processed using a custom-written Matlab script. RESULTS Hyperpolarized 6-phosphogluconolactone (6PG), the metabolic product from δ-[1-13C] gluconolactone via the PPP, was significantly reduced in TERT or GABPB1 silenced cells compared to control cells in both U251 models. The positive correlation between TERT expression and 6PG level was confirmed by linear regression analysis. Hyperpolarized 6PG production in both tumor models was also significantly reduced in TERT or GABPB1-silenced tumors compared to controls. CONCLUSION We successfully visualized TERT-associated changes in dynamic PPP metabolism in a GBM model in cells and in vivo. Hyperpolarized δ-[1-13C] gluconolactone is a potential tool for monitoring TERT expression in GBM with TERT promoter mutations.

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.

A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder

BackgroundMajor depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD.Methods/designThis double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD. Eligible participants with MDD (n = 48) will be stratified into the high and low inflammatory groups according to the levels of high-sensitivity C-reactive protein (hs-CRP) and then randomized to receive LDN or placebo for an initial 12 weeks, followed by a further 12 weeks during which all participants will receive LDN. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, and 24 weeks, to assess the effectiveness of the anti-depressant response. The secondary outcomes include the use of MRI techniques including quantitative magnetization transfer (qMT), echo-planar spectroscopic imaging (EPSI), and diffusion-weighted imaging (DWI) to help to elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. Electroencephalography, blood samples, cognitive tasks, and additional questionnaires will also be used to determine if there is a specific profile of symptoms in individuals with inflammatory MDD. Healthy participants (n = 24) will be recruited for baseline outcome measures only, to enable comparison with patients with MDD.DiscussionThis trial contributes to the literature on inflammation in MDD, including the understanding of the pathophysiology and efficacy of anti-inflammatory treatments. The investigation of inflammatory mechanisms in MDD is an important first step in the development of biomarkers to classify patient sub-groups, increase the accuracy of diagnosis, and tailor the approach to patients in clinical practice. This study may provide evidence of the benefit of LDN for the groups in whom conventional anti-depressants are ineffective and lead the way for translation into clinical practice.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12622000881730. Registered on 21 June 2022

Artifact suppression in readout-segmented consistentK-tspace EPSI (RS-COKE) for fast 1 H spectroscopic imagingat7 T.

Fast proton (1 H) MRSI is an important diagnostic tool for clinical investigations, providing metabolic and spatial information. MRSI at 7T benefits from increased SNR and improved separation of peaks but requires larger spectral widths. RS-COKE (Readout-Segmented Consistent K-t space Epsi) is an echo planar spectroscopic imaging (Epsi) variant capable to support the spectral width required for human brain metabolites spectra at 7T. However, mismatches between readout segments lead to artifacts, particularly when subcutaneous lipid signals are not suppressed. In this study, these mismatches and their effects are analyzed and reduced. The following corrections to the data were performed: i) frequency-dependent phase corrections; ii) k-space trajectory corrections, derived from short reference scans; and iii) smoothing of data at segment transitions to mitigate the effect of residual mismatches. The improvement was evaluated by performing single-slice RS-COKE on a head-shaped phantom with a "lipid" layer and healthy subjects, using varying resolutions and durations ranging from 4.1 × 4.7 × 15 mm3 in 5:46 min to 3.1 × 3.3 × 15 mm3 in 13:07 min. Artifacts arising from the readout-segmented acquisition were substantially reduced, thus providing high-quality spectroscopic imaging in phantom and human scans. LCModel fitting of the human data resulted in a relative Cramer-Rao lower bounds within 6% for NAA, Cr, and Cho images in the majority of the voxels. Using the new reference scans and reconstruction steps, RS-COKE was able to deliver fast 1 H MRSI at 7T, overcoming the spectral width limitation of standard EPSI at this field strength.

Active conductive head cooling of normal and infarcted brain: A magnetic resonance spectroscopy imaging study

Active conductive head cooling is a simple and non-invasive intervention that may slow infarct growth in ischemic stroke. We investigated the effect of active conductive head cooling on brain temperature using whole brain echo-planar spectroscopic imaging. A cooling cap (WElkins Temperature Regulation System, 2nd Gen) was used to administer cooling for 80 minutes to healthy volunteers and chronic stroke patients. Whole brain echo-planar spectroscopic imaging scans were obtained before and after cooling. Brain temperature was estimated using the Metabolite Imaging and Data Analysis System software package, which allows voxel-level temperature calculations using the chemical shift difference between metabolite (N-acetylaspartate, creatine, choline) and water resonances. Eleven participants (six healthy volunteers, five post-stroke) underwent 80 ± 5 minutes of cooling. The average temperature of the coolant was 1.3 ± 0.5°C below zero. Significant reductions in brain temperature (ΔT = –0.9 ± 0.7°C, P = 0.002), and to a lesser extent, rectal temperature (ΔT = –0.3 ± 0.1°C, P = 0.03) were observed. Exploratory analysis showed that the occipital lobes had the greatest reduction in temperature (ΔT = –1.5 ± 1.2°C, P = 0.002). Regions of infarction had similar temperature reductions to the contralateral normal brain. Future research could investigate the feasibility of head cooling as a potential neuroprotective strategy in patients being considered for acute stroke therapies.

Metabolite-cycled echo-planar spectroscopic imaging ofthehuman heart.

PurposeSpectroscopic imaging could provide insights into regional cardiac triglyceride variations, but is hampered by relatively long scan times. It is proposed to synergistically combine echo‐planar spectroscopic imaging (EPSI) with motion‐adapted gating, weighted acquisition and metabolite cycling to reduce scan times to less than 10 min while preserving spatial‐spectral quality. The method is compared to single‐voxel measurements and to metabolite‐cycled EPSI with conventional acquisition for assessing triglyceride‐to‐water (TG/W) ratios in the human heart.MethodsMeasurements were performed on 10 healthy volunteers using a clinical 1.5T system. EPSI data was acquired both without and with motion‐adapted gating in combination with weighted acquisition to assess TG/W ratios and relative Cramér‐Rao lower bounds (CRLB) of TG. For comparison, single‐voxel (PRESS) spectra were acquired in the interventricular septum.ResultsBland–Altman analyses did not show a significant bias in TG/W when comparing both metabolite‐cycled EPSI methods to PRESS for any of the cardiac segments. Scan time was 8.05 ± 2.06 min and 17.91 ± 3.93 min for metabolite‐cycled EPSI with and without motion‐adapted gating and weighted acquisition, respectively, while relative CRLB of TG did not differ significantly between the two methods for any of the cardiac segments.ConclusionsMetabolite‐cycled EPSI with motion‐adapted gating and weighted acquisition allows detecting TG/W ratios in different regions of the in vivo human heart. Scan time is reduced by more than 2‐fold to less than 10 min as compared to conventional acquisition, while keeping the quality of TG fitting constant.

Proton metabolic mapping of the brain at 7T using a two-dimensional free induction decay-echo-planar spectroscopic imaging readout with lipid suppression.

The increased signal‐to‐noise ratio (SNR) and chemical shift dispersion at high magnetic fields (≥7 T) have enabled neuro‐metabolic imaging at high spatial resolutions. To avoid very long acquisition times with conventional magnetic resonance spectroscopic imaging (MRSI) phase‐encoding schemes, solutions such as pulse‐acquire or free induction decay (FID) sequences with short repetition time and inner volume selection methods with acceleration (echo‐planar spectroscopic imaging [EPSI]), have been proposed. With the inner volume selection methods, limited spatial coverage of the brain and long echo times may still impede clinical implementation. FID‐MRSI sequences benefit from a short echo time and have a high SNR per time unit; however, contamination from strong extra‐cranial lipid signals remains a problem that can hinder correct metabolite quantification. L2‐regularization can be applied to remove lipid signals in cases with high spatial resolution and accurate prior knowledge. In this work, we developed an accelerated two‐dimensional (2D) FID‐MRSI sequence using an echo‐planar readout and investigated the performance of lipid suppression by L2‐regularization, an external crusher coil, and the combination of these two methods to compare the resulting spectral quality in three subjects. The reduction factor of lipid suppression using the crusher coil alone varies from 2 to 7 in the lipid region of the brain boundary. For the combination of the two methods, the average lipid area inside the brain was reduced by 2% to 38% compared with that of unsuppressed lipids, depending on the subject's region of interest. 2D FID‐EPSI with external lipid crushing and L2‐regularization provides high in‐plane coverage and is suitable for investigating brain metabolite distributions at high fields.