Comparison of seven modelling algorithms for γ-aminobutyric acid-edited proton magnetic resonance spectroscopy.

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Motion correction methods for MRS: experts' consensus recommendations.

Long acquisition times due to intrinsically low signal-to-noise ratio and the need for highly homogeneous B0 field make MRS particularly susceptible to motion or scanner instability compared with MRI. Motion-induced changes in both localization and shimming (ie B0 homogeneity) degrade MRS data quality. To mitigate the effects of motion three approaches can be employed: (1) subject immobilization, (2) retrospective correction, and (3) prospective real-time correction using internal and/or external tracking methods. Prospective real-time correction methods can simultaneously update localization and the B0 field to improve MRS data quality. While localization errors can be corrected with both internal (navigators) and external (optical camera, NMR probes) tracking methods, the B0 field correction requires internal navigator methods to measure the B0 field inside the imaged volume and the possibility to update the scanner shim hardware in real time. Internal and external tracking can rapidly update the MRS localization with submillimeter and subdegree precision, while scanner frequency and first-order shims of scanner hardware can be updated by internal methods every sequence repetition. These approaches are most well developed for neuroimaging, for which rigid transformation is primarily applicable. Real-time correction greatly improves the stability of MRS acquisition and quantification, as shown in clinical studies on subjects prone to motion, including children and patients with movement disorders, enabling robust measurement of metabolite signals including those with low concentrations, such as gamma-aminobutyric acid and glutathione. Thus, motion correction is recommended for MRS users and calls for tighter integration and wider availability of such methods by MR scanner manufacturers.

Contribution of macromolecules to brain 1 H MR spectra: Experts' consensus recommendations.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Activation volume vs BOLD signal change as measures of fMRI activation - Its impact on GABA - fMRI activation correlation.

PURPOSE: To explore the relative robustness of functional MRI (fMRI) activation volume and blood oxygen level-dependent (BOLD) signal change as fMRI metric, and to study the effect of relative robustness on the correlation between fMRI activation and cortical gamma amino butyric acid (GABA) in healthy controls and patients with multiple sclerosis (MS). METHODS: fMRI data were acquired from healthy controls and patients with MS, with the subjects peforming self paced bilateral finger tapping in block design. GABA spectroscopy was performed with voxel placed on the area of maximum activation during fMRI. Activation volume and BOLD signal changes at primary motor cortex (M1), as well as GABA concentration were calculated for each patient. RESULTS: Activation volume correlated with BOLD signal change in healthy controls, but no such correlation was observed in patients with MS. This difference was likely the result of higher intersubject noise variance in the patient population. GABA concentration correlated with M1 activation volume in patients but not in controls, and did not correlate with any fMRI metric in patients or controls. CONCLUSION: Our data suggest that activation volume is a more robust measure than BOLD signal change in a group with high intersubject noise variance as in patients with MS. Additionally, this study demonstrated difference in correlation behavior between GABA concentration and the 2 fMRI metrics in patients with MS, suggesting that GABA - activation volume correlation is more appropriate measure in the patient group.

Sacral Neuromodulation Device Heating During Lumbar and Pelvic Magnetic Resonance Imaging-a Phantom Study.

OBJECTIVE: To evaluate radiofrequency-induced temperature rises associated with performing lumbar and pelvic magnetic resonance imaging (MRI) studies with an implanted sacral neuromodulation device using a phantom model. MATERIALS AND METHODS: An accepted phantom model of radiofrequency-induced heating in human tissue was used to measure the temperature rise in the stimulator lead electrodes and impulse generator under the conditions used during routine clinical lumbar and pelvic MRIs in a 1.5Tesla MRI scanner. Testing configurations included an intact device (tined lead connected to generator), an intact lead, and a lead fragment (model of lead fracture). Variations in the position of the phantom relative to the scanner were also tested. RESULTS: During testing with the intact device or the lead fragment no significant heating was detected. In contrast, the isolated intact lead model showed heating up to 5°C. CONCLUSION: These tests provide preliminary evidence that the risk of heating is low for clinical lumbar and pelvic MRI at 1.5-Tesla with an intact sacral neuromodulation device system and with a fractured lead. However, there is a significant temperature change in the intact lead model.

Real-Time Changes in Brain Activity during Sacral Neuromodulation for Overactive Bladder.

PURPOSE: We performed functional magnetic resonance imaging to identify changes in brain activity during sacral neuromodulation in women with overactive bladder who were responsive to therapy. MATERIALS AND METHODS: Women recruited into the study had nonneurogenic refractory overactive bladder, responded to sacral neuromodulation and had had a stable program for at least 3 months with no subsequent overactive bladder treatment. Enrolled patients completed validated symptom and quality of life instruments before functional magnetic resonance imaging. Stimulus settings were recorded, devices were switched off for a 5-day washout and instruments were repeated. Three functional magnetic resonance imaging scans with simultaneous sacral neuromodulation stimulation were performed below, at and above stimulus sensory threshold using a block design. This yielded brain activity maps represented by changes in blood oxygenation level dependence. A total of 5 stimulator off and 4 stimulator on cycles of 42 seconds each were imaged. Group analysis was done using a single voxel p value of 0.05 with a false-positive error of 0.05 on cluster analysis. RESULTS: Six of the 13 patients enrolled completed functional magnetic resonance imaging. Median age was 52 years (range 36 to 64). Urinary symptoms and voiding diary data worsened with washout. Overall brain activation generally progressed with increasing stimulation amplitude. However, activation of the right inferior frontal gyrus remained stable while deactivation of the pons and the periacqueductal gray matter only occurred with subsensory stimulation. Sensory stimulation activated the insula but deactivated the medial and superior parietal lobes. Suprasensory stimulation activated multiple structures and the expected S3 somatosensory region. All devices had normal impedance after functional magnetic resonance imaging. CONCLUSIONS: Functional magnetic resonance imaging confirmed that sacral neuromodulation influences brain activity in women with overactive bladder who responded to therapy. These changes varied with stimulus intensity.

Safety of externally stimulated intracranial electrodes during functional MRI at 1.5T.

Surgical resection of the epileptogenic zone (EZ) is a potential cure for medically refractory focal epilepsy. Proper identification of the EZ is essential for such resection. Synergistic application of functional magnetic resonance imaging (fMRI) simultaneously with stimulation of a single externalized intracranial stereotactic EEG (SEEG) electrode has the potential to improve identification of the EZ. While most EEG-fMRI studies use the electrodes passively to record electrical activity, it is possible to stimulate the brain using the electrodes by connecting them with conducting cables to the stimulation hardware. In this study, we investigated the effect of MRI-induced heating on a single SEEG electrode and its sensitivity to geometry, configuration, and associated connections required for the stimulation. The temperature increase of a single electrode embedded within a gel phantom and connected to an external stimulation system was measured during 1.5T MRI scans using adjacent fluoroptic temperature sensors. A receive-only split-array head coil and a transmit-receive head coil were used for testing. Sequences included a standard localizer, T1-weighted axial fast low-angle shot (FLASH), gradient echo-planar imaging (GE-EPI) axial fMRI, and a high specific absorption rate T2-weighted turbo spin-echo (TSE) axial scan. Variations of the electrode location and connecting cable configuration were tested. No unacceptable heating was observed with the standard sequences used for evaluation of the EZ. Considerable heating (up to 14°C) was observed with the TSE sequence, which is not used clinically. The temperature increase was insignificant (<0.05°C) for electrode contacts closest to the isocenter and connecting cables lying along the isocenter, and varied with configurations of the connecting cable assembly. Simultaneous intracranial electrode stimulation during fMRI using an externalized stimulation system may be safe with strict adherence to settings tested prior to the fMRI. Localizer, FLASH, and GE-EPI fMRI may be safely performed in patients with a single SEEG electrode following the configurations tested in this study, but high SAR TSE scans should not be performed in these patients.

In vivo magnetic resonance spectroscopy measurement of gray-matter and white-matter gamma-aminobutyric acid concentration in sensorimotor cortex using a motion-controlled MEGA point-resolved spectroscopy sequence.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain. Understanding the GABA concentration, in vivo, is important to understand normal brain function. Using MEGA point-resolved spectroscopy sequence with interleaved water scans to detect subject motion, GABA level of sensorimotor cortex was measured using a voxel identified from a functional magnetic resonance imaging scan. The GABA level in a 20×20×20-mm(3) voxel consisting of 37%±7% gray matter, 52%±12% white matter and 11%±8% cerebrospinal fluid in the sensorimotor region was measured to be 1.43±0.48 mM. In addition, using linear regression analysis, GABA concentrations within gray and white matter were calculated to be 2.87±0.61 and 0.33±0.11 mM, respectively.

Functional pathway-defined MRI diffusion measures reveal increased transverse diffusivity of water in multiple sclerosis.

The diffusion properties of water are sensitive to microscopic changes in the white matter of multiple sclerosis (MS) patients. Typical MRI measures of disease burden in MS demonstrate modest to poor correlation with disability. Functional MRI and DTI-based fiber tracking were used to define the interhemispheric white matter pathway connecting bilateral supplementary motor areas (SMA) in 16 MS patients sand 16 control subjects. Fractional anisotropy (FA), mean diffusivity (MD), longitudinal (lambda(1)) and transverse diffusivity (lambda(2)) were measured along this pathway in all subjects. Mean FA was 0.587 +/- 0.032 for patients and 0.608 +/- 0.020 for controls (P < 0.02). Mean MD was (0.821 +/- 0.055) x 10(-3) mm(2) s(-1) for patients and (0.770 +/- 0.020) x 10(-3) mm(2) s(-1) for controls (P < 0.004). Mean lambda(1) values were (1.462 +/- 0.099) x 10(-3) mm(2) s(-1) for patients and (1.400 +/- 0.034) x 10(-3) mm(2) s(-1) for controls (P < 0.02). Mean lambda(2) values were (0.500 +/- 0.047) x 10(-3) mm(2) s(-1) for patients and (0.454 +/- 0.027) x 10(-3) mm(2) s(-1) for controls (P < 0.001). In addition, the correlation between the Multiple Sclerosis Functional Composite (MSFC) and transverse diffusivity was -0.341 (P < 0.05). The component test of the MSFC most related to the SMA pathway studied with our MRI method (Nine-hole Peg Test) showed significant correlation with transverse diffusivity (r = 0.392, P < 0.02), indicating that probing functional pathways with MRI measures can lead to a better reflection of disease status.

Cardiac-induced physiologic noise in tissue is a direct observation of cardiac-induced fluctuations.

Recent studies have shown that in certain cases, cardiac and respiratory rate fluctuations in BOLD-weighted MRI time courses may be an artifact unique to rapid sampled acquisitions and may not be present in longer repetition-time acquisitions. The implication of this is that, in these cases, cardiac and respiratory rate fluctuations are not aliased into data that undersample these effects and do not affect the resulting time course measurements. In this study, we show that these cases are specific to regions of large cerebrospinal fluid content and are not generally true for gray matter regions of the brain. We demonstrate that in many brain regions of interest, these fluctuations are directly observed as BOLD fluctuations and thus will affect measurements that undersample these effects.