Repeat it without me: Crowdsourcing the T1 mapping common ground via the ISMRM reproducibility challenge.

PURPOSE: T1 mapping is a widely used quantitative MRI technique, but its tissue-specific values remain inconsistent across protocols, sites, and vendors. The ISMRM Reproducible Research and Quantitative MR study groups jointly launched a challenge to assess the reproducibility of a well-established inversion-recovery T1 mapping technique, using acquisition details from a seminal T1 mapping paper on a standardized phantom and in human brains. METHODS: The challenge used the acquisition protocol from Barral et al. (2010). Researchers collected T1 mapping data on the ISMRM/NIST phantom and/or in human brains. Data submission, pipeline development, and analysis were conducted using open-source platforms. Intersubmission and intrasubmission comparisons were performed. RESULTS: Eighteen submissions (39 phantom and 56 human datasets) on scanners by three MRI vendors were collected at 3 T (except one, at 0.35 T). The mean coefficient of variation was 6.1% for intersubmission phantom measurements, and 2.9% for intrasubmission measurements. For humans, the intersubmission/intrasubmission coefficient of variation was 5.9/3.2% in the genu and 16/6.9% in the cortex. An interactive dashboard for data visualization was also developed: https://rrsg2020.dashboards.neurolibre.org. CONCLUSION: The T1 intersubmission variability was twice as high as the intrasubmission variability in both phantoms and human brains, indicating that the acquisition details in the original paper were insufficient to reproduce a quantitative MRI protocol. This study reports the inherent uncertainty in T1 measures across independent research groups, bringing us one step closer to a practical clinical baseline of T1 variations in vivo.

Promise and pitfalls of g-ratio estimation with MRI.

The fiber g-ratio is the ratio of the inner to the outer diameter of the myelin sheath of a myelinated axon. It has a limited dynamic range in healthy white matter, as it is optimized for speed of signal conduction, cellular energetics, and spatial constraints. In vivo imaging of the g-ratio in health and disease would greatly increase our knowledge of the nervous system and our ability to diagnose, monitor, and treat disease. MRI based g-ratio imaging was first conceived in 2011, and expanded to be feasible in full brain white matter with preliminary results in 2013. This manuscript reviews the growing g-ratio imaging literature and speculates on future applications. It details the methodology for imaging the g-ratio with MRI, and describes the known pitfalls and challenges in doing so.

Sensitivity regularization of the Cramér-Rao lower bound to minimize B1 nonuniformity effects in quantitative magnetization transfer imaging.

PURPOSE: To develop and validate a regularization approach of optimizing B1 insensitivity of the quantitative magnetization transfer (qMT) pool-size ratio (F). METHODS: An expression describing the impact of B1 inaccuracies on qMT fitting parameters was derived using a sensitivity analysis. To simultaneously optimize for robustness against noise and B1 inaccuracies, the optimization condition was defined as the Cramér-Rao lower bound (CRLB) regularized by the B1 -sensitivity expression for the parameter of interest (F). The qMT protocols were iteratively optimized from an initial search space, with and without B1 regularization. Three 10-point qMT protocols (Uniform, CRLB, CRLB+B1 regularization) were compared using Monte Carlo simulations for a wide range of conditions (e.g., SNR, B1 inaccuracies, tissues). RESULTS: The B1 -regularized CRLB optimization protocol resulted in the best robustness of F against B1 errors, for a wide range of SNR and for both white matter and gray matter tissues. For SNR = 100, this protocol resulted in errors of less than 1% in mean F values for B1 errors ranging between -10 and 20%, the range of B1 values typically observed in vivo in the human head at field strengths of 3 T and less. Both CRLB-optimized protocols resulted in the lowest σF values for all SNRs and did not increase in the presence of B1 inaccuracies. CONCLUSION: This work demonstrates a regularized optimization approach for improving the robustness of auxiliary measurements (e.g., B1 ) sensitivity of qMT parameters, particularly the pool-size ratio (F). Predicting substantially less B1 sensitivity using protocols optimized with this method, B1 mapping could even be omitted for qMT studies primarily interested in F.

B1 -sensitivity analysis of quantitative magnetization transfer imaging.

PURPOSE: To evaluate the sensitivity of quantitative magnetization transfer (qMT) fitted parameters to B1 inaccuracies, focusing on the difference between two categories of T1 mapping techniques: B1 -independent and B1 -dependent. METHODS: The B1 -sensitivity of qMT was investigated and compared using two T1 measurement methods: inversion recovery (IR) (B1 -independent) and variable flip angle (VFA), B1 -dependent). The study was separated into four stages: 1) numerical simulations, 2) sensitivity analysis of the Z-spectra, 3) healthy subjects at 3T, and 4) comparison using three different B1 imaging techniques. RESULTS: For typical B1 variations in the brain at 3T (±30%), the simulations resulted in errors of the pool-size ratio (F) ranging from -3% to 7% for VFA, and -40% to > 100% for IR, agreeing with the Z-spectra sensitivity analysis. In healthy subjects, pooled whole-brain Pearson correlation coefficients for F (comparing measured double angle and nominal flip angle B1 maps) were ρ = 0.97/0.81 for VFA/IR. CONCLUSION: This work describes the B1 -sensitivity characteristics of qMT, demonstrating that it varies substantially on the B1 -dependency of the T1 mapping method. Particularly, the pool-size ratio is more robust against B1 inaccuracies if VFA T1 mapping is used, so much so that B1 mapping could be omitted without substantially biasing F. Magn Reson Med 79:276-285, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

B1 mapping for bias-correction in quantitative T1 imaging of the brain at 3T using standard pulse sequences.

PURPOSE: B1 mapping is important for many quantitative imaging protocols, particularly those that include whole-brain T1 mapping using the variable flip angle (VFA) technique. However, B1 mapping sequences are not typically available on many magnetic resonance imaging (MRI) scanners. The aim of this work was to demonstrate that B1 mapping implemented using standard scanner product pulse sequences can produce B1 (and VFA T1 ) maps comparable in quality and acquisition time to advanced techniques. MATERIALS AND METHODS: Six healthy subjects were scanned at 3.0T. An interleaved multislice spin-echo echo planar imaging double-angle (EPI-DA) B1 mapping protocol, using a standard product pulse sequence, was compared to two alternative methods (actual flip angle imaging, AFI, and Bloch-Siegert shift, BS). Single-slice spin-echo DA B1 maps were used as a reference for comparison (Ref. DA). VFA flip angles were scaled using each B1 map prior to fitting T1 ; the nominal flip angle case was also compared. RESULTS: The pooled-subject voxelwise correlation (ρ) for B1 maps (BS/AFI/EPI-DA) relative to the reference B1 scan (Ref. DA) were ρ = 0.92/0.95/0.98. VFA T1 correlations using these maps were ρ = 0.86/0.88/0.96, much better than without B1 correction (ρ = 0.53). The relative error for each B1 map (BS/AFI/EPI-DA/Nominal) had 95th percentiles of 5/4/3/13%. CONCLUSION: Our findings show that B1 mapping implemented using product pulse sequences can provide excellent quality B1 (and VFA T1 ) maps, comparable to other custom techniques. This fast whole-brain measurement (∼2 min) can serve as an excellent alternative for researchers without access to advanced B1 pulse sequences. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1673-1682.

In vivo histology of the myelin g-ratio with magnetic resonance imaging.

The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment.

On the accuracy of T1 mapping: searching for common ground.

PURPOSE: There are many T1 mapping methods available, each of them validated in phantoms and reporting excellent agreement with literature. However, values in literature vary greatly, with T1 in white matter ranging from 690 to 1100 ms at 3 Tesla. This brings into question the accuracy of one of the most fundamental measurements in quantitative MRI. Our goal was to explain these variations and look into ways of mitigating them. THEORY AND METHODS: We evaluated the three most common T1 mapping methods (inversion recovery, Look-Locker, and variable flip angle) through Bloch simulations, a white matter phantom and the brains of 10 healthy subjects (single-slice). We pooled the T1 histograms of the subjects to determine whether there is a sequence-dependent bias and whether it is reproducible across subjects. RESULTS: We found good agreement between the three methods in phantoms, but poor agreement in vivo, with the white matter T1 histogram peak in healthy subjects varying by more than 30% depending on the method used. We also found that the pooled brain histograms displayed three distinct white matter peaks, with Look-Locker consistently underestimating, and variable flip angle overestimating the inversion recovery T1 values. The Bloch simulations indicated that incomplete spoiling and inaccurate B1 mapping could account for the observed differences. CONCLUSION: We conclude that the three most common T1 mapping protocols produce stable T1 values in phantoms, but not in vivo. To improve the accuracy of T1 mapping, we recommend that sites perform in vivo validation of their T1 mapping method against the inversion recovery reference method, as the first step toward developing a robust calibration scheme.

Reproducible Research Practices in Magnetic Resonance Neuroimaging: A Review Informed by Advanced Language Models.

MRI has progressed significantly with the introduction of advanced computational methods and novel imaging techniques, but their wider adoption hinges on their reproducibility. This concise review synthesizes reproducible research insights from recent MRI articles to examine the current state of reproducibility in neuroimaging, highlighting key trends and challenges. It also provides a custom generative pretrained transformer (GPT) model, designed specifically for aiding in an automated analysis and synthesis of information pertaining to the reproducibility insights associated with the articles at the core of this review.

The Past, Present, and Future of the Brain Imaging Data Structure (BIDS).

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Measurement of 129Xe gas apparent diffusion coefficient anisotropy in an elastase-instilled rat model of emphysema.

Hyperpolarized noble gas ((3)He and (129)Xe) apparent diffusion coefficient (ADC) measurements have shown remarkable sensitivity to microstructural (i.e., alveolar) changes in the lung, particularly emphysema. The ADC of hyperpolarized noble gases depends strongly on the diffusion time (Δ), and (3)He ADC has been shown to be anisotropic for Δ ranging from a few milliseconds down to a few hundred microseconds. In this study, the anisotropic nature of (129)Xe diffusion and its dependence on Δ were investigated both numerically, in a budded cylinder model, and in vivo, in an elastase-instilled rat model of emphysema. Whole lung longitudinal ADC (D(L)) and transverse ADC (D(T)) were measured for Δ = 6, 50, and 100 ms at 73.5 mT, and correlated with measurements of the mean linear intercept (L(m)) obtained from lung histology. A significant increase (P = 0.0021) in D(T) was measured for Δ = 6 ms between the sham (0.0021 ± 0.0005 cm(2)/s) and elastase-instilled (0.005 ± 0.001 cm(2)/s) cohorts, and a strong correlation was measured between D(T) (Δ = 6 ms) and L(m), with a Pearson's correlation coefficient of 0.90. This study confirms that (129)Xe D(T) increases correlate with alveolar space enlargement due to elastase instillation in rats.

Mapping of (3) He apparent diffusion coefficient anisotropy at sub-millisecond diffusion times in an elastase-instilled rat model of emphysema.

Hyperpolarized (3) He gas can provide detailed anatomical maps of the macroscopic airways in the lungs (i.e., ventilation) as well as insight into the lung microstructure through the apparent diffusion coefficient. In particular, the apparent diffusion coefficient of (3) He in the lung exhibits anisotropic effects that depend on diffusion time (δ), and it has been shown to be extraordinarily sensitive to enlargement in terminal airways and alveoli associated with emphysema. In this study, the anisotropic nature of the (3) He apparent diffusion coefficient is studied in a rat model of emphysema, based on elastase instillation, specifically for δ values less than one millisecond. Longitudinal (D(L) ) and transverse (D(T) ) diffusion coefficients were mapped at δ = 360 µs and δ = 800 µs based on a cylinder model of lung structure and correlated with histological measurement of alveolar damage based on mean linear intercept (L(m) ). Whole-lung mean D(T) measured at δ = 360 µs in the elastase-instilled rat lungs (0.14 ± 0.09 cm(2) /s) demonstrated the most significant increase (p = 0.00195) compared to the sham-instilled cohort (0.06 ± 0.06 cm(2) /s) and had a strong linear correlation with L(m) (Pearson's correlation coefficient of 0.9). These results suggest that measurement of (3) He apparent diffusion coefficient anisotropy, specifically D(T) , can provide a sensitive indicator of emphysema, particularly at very short diffusion times (δ = 360 µs).

qMRI-BIDS: An extension to the brain imaging data structure for quantitative magnetic resonance imaging data.

The Brain Imaging Data Structure (BIDS) established community consensus on the organization of data and metadata for several neuroimaging modalities. Traditionally, BIDS had a strong focus on functional magnetic resonance imaging (MRI) datasets and lacked guidance on how to store multimodal structural MRI datasets. Here, we present and describe the BIDS Extension Proposal 001 (BEP001), which adds a range of quantitative MRI (qMRI) applications to the BIDS. In general, the aim of qMRI is to characterize brain microstructure by quantifying the physical MR parameters of the tissue via computational, biophysical models. By proposing this new standard, we envision standardization of qMRI through multicenter dissemination of interoperable datasets. This way, BIDS can act as a catalyst of convergence between qMRI methods development and application-driven neuroimaging studies that can help develop quantitative biomarkers for neural tissue characterization. In conclusion, this BIDS extension offers a common ground for developers to exchange novel imaging data and tools, reducing the entrance barrier for qMRI in the field of neuroimaging.

Reduced Axon Calibre in the Associative Striatum of the Sapap3 Knockout Mouse.

Pathological repetitive behaviours are a common feature of various neuropsychiatric disorders, including compulsions in obsessive-compulsive disorder or tics in Gilles de la Tourette syndrome. Clinical research suggests that compulsive-like symptoms are related to associative cortico-striatal dysfunctions, and tic-like symptoms to sensorimotor cortico-striatal dysfunctions. The Sapap3 knockout mouse (Sapap3-KO), the current reference model to study such repetitive behaviours, presents both associative as well as sensorimotor cortico-striatal dysfunctions. Previous findings point to deficits in both macro-, as well as micro-circuitry, both of which can be affected by neuronal structural changes. However, to date, structural connectivity has not been analysed. Hence, in the present study, we conducted a comprehensive structural characterisation of both associative and sensorimotor striatum as well as major cortical areas connecting onto these regions. Besides a thorough immunofluorescence study on oligodendrocytes, we applied AxonDeepSeg, an open source software, to automatically segment and characterise myelin thickness and axon area. We found that axon calibre, the main contributor to changes in conduction speed, is specifically reduced in the associative striatum of the Sapap3-KO mouse; myelination per se seems unaffected in associative and sensorimotor cortico-striatal circuits.

A simple and robust method for automating analysis of naïve and regenerating peripheral nerves.

BACKGROUND: Manual axon histomorphometry (AH) is time- and resource-intensive, which has inspired many attempts at automation. However, there has been little investigation on implementation of automated programs for widespread use. Ideally such a program should be able to perform AH across imaging modalities and nerve states. AxonDeepSeg (ADS) is an open source deep learning program that has previously been validated in electron microscopy. We evaluated the robustness of ADS for peripheral nerve axonal histomorphometry in light micrographs prepared using two different methods. METHODS: Axon histomorphometry using ADS and manual analysis (gold-standard) was performed on light micrographs of naïve or regenerating rat median nerve cross-sections prepared with either toluidine-resin or osmium-paraffin embedding protocols. The parameters of interest included axon count, axon diameter, myelin thickness, and g-ratio. RESULTS: Manual and automatic ADS axon counts demonstrated good agreement in naïve nerves and moderate agreement on regenerating nerves. There were small but consistent differences in measured axon diameter, myelin thickness and g-ratio; however, absolute differences were small. Both methods appropriately identified differences between naïve and regenerating nerves. ADS was faster than manual axon analysis. CONCLUSIONS: Without any algorithm retraining, ADS was able to appropriately identify critical differences between naïve and regenerating nerves and work with different sample preparation methods of peripheral nerve light micrographs. While there were differences between absolute values between manual and ADS, ADS performed consistently and required much less time. ADS is an accessible and robust tool for AH that can provide consistent analysis across protocols and nerve states.

Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1.

There is growing evidence for involvement of members of the cyclin-dependent kinase (Cdk) family in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults. After our recent report that a deregulation of Cdk5 activity by p25 may contribute to pathogenesis of amyotrophic lateral sclerosis (ALS), we further examined the possible involvement of other Cdks in mice expressing a mutant form of superoxide dismutase (SOD1(G37R)) linked to ALS. No substantial changes in Cdk2 or Cdk6 distribution and kinase activities were detected in spinal motor neurons from SOD1(G37R) mice when compared with normal mice. Of particular interest was the upregulation and mislocalization of Cdk4, a regulator of the G1-S checkpoint of the cell cycle, in motor neurons of SOD1(G37R) mice. The increase of Cdk4 activity in SOD1(G37R) mice was associated with an increase in nuclear Cdk4, cyclin D1, its coactivator, and with the abnormal phosphorylation of the retinoblastoma (Rb) protein at Cdk phosphorylation sites. Pharmacological treatment of SOD1(G37R) mice with minocycline, a compound that attenuates microgliosis and slows down disease, lessened the dysregulation of Cdk5/Cdk4 and the phosphorylation of Rb. Interestingly, phospho-Rb was immunoprecipitated with anti-Cdk4 but not with anti-Cdk5 antibodies, suggesting a key role for Cdk4 in the phosphorylation of Rb. Remarkably, the overexpression of a transgene coding for human neurofilament H, a phosphorylation sink for deregulated Cdk5 activity by p25, resulted in a reduction in levels of nuclear Cdk4 and Rb phosphorylation. These results indicate that a cell cycle signaling at the neuronal G1-S checkpoint subsequent to Cdk5 deregulation may constitute a critical step of the neuronal death pathway in ALS caused by mutant SOD1.

Quantitative analysis of the myelin g-ratio from electron microscopy images of the macaque corpus callosum.

We provide a detailed morphometric analysis of eight transmission electron micrographs (TEMs) obtained from the corpus callosum of one cynomolgus macaque. The raw TEM images are included in the article, along with the distributions of the axon caliber and the myelin g-ratio in each image. The distributions are analyzed to determine the relationship between axon caliber and g-ratio, and compared against the aggregate metrics (myelin volume fraction, fiber volume fraction, and the aggregate g-ratio), as defined in the accompanying research article entitled 'In vivo histology of the myelin g-ratio with magnetic resonance imaging' (Stikov et al., NeuroImage, 2015).

K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK.

K252a is best known as a Trk inhibitor, but is also a neuroprotective compound. CEP1347, a K252a derivative, retains neuroprotective properties, but does not inhibit TrkA. CEP1347 has recently been shown to directly inhibit MAPKKKs, including MLK3, but the effect of K252a on MAPKKKs remains unknown. K252a and CEP1347 not only prevent death, but also facilitate neurite outgrowth and maintenance, somal hypertrophy, and neurotransmitter synthesis. The biochemical basis for these trophic effects remains unknown. We have compared the effects of CEP1347 and K252a on MLK and JNK signaling and on neurotrophic pathways that support survival and growth. Our data show that K252a is a potent inhibitor of MLK3 activity in vivo and in vitro (IC(50) approximately 5 nm). However, we also found that K252a and CEP1347 activate Akt and ERK and show that blockade of phosphatidylinositol 3-kinase or MEK activity ablates the effect of K252a and CEP1347 on cell survival. Activation of Akt and ERK occurs through an MLK-independent pathway that may involve c-Src. Together, these data show that the neuroprotective and neurotrophic effects of K252a and CEP1347 involve activation of several neurotrophic signaling pathways.