This review describes targeted magnetic resonance imaging (tMRI) of small changes in the T₁ and the spatial properties of normal or near normal appearing white or gray matter in disease of the brain. It employs divided subtracted inversion recovery (dSIR) and divided reverse subtracted inversion recovery (drSIR) sequences to increase the contrast produced by small changes in T₁ by up to 15 times compared to conventional T₁-weighted inversion recovery (IR) sequences such as magnetization prepared-rapid acquisition gradient echo (MP-RAGE). This increase in contrast can be used to reveal disease with only small changes in T₁ in normal appearing white or gray matter that is not apparent on conventional MP-RAGE, T₂-weighted spin echo (T₂-wSE) and/or fluid attenuated inversion recovery (T₂-FLAIR) images. The small changes in T₁ or T₂ in disease are insufficient to produce useful contrast with conventional sequences. To produce high contrast dSIR and drSIR sequences typically need to be targeted for the nulling TI of normal white or gray matter, as well as for the sign and size of the change in T₁ in these tissues in disease. The dSIR sequence also shows high signal boundaries between white and gray matter. dSIR and drSIR are essentially T₁ maps. There is a nearly linear relationship between signal and T₁ in the middle domain (mD) of the two sequences which includes T₁s between the nulling T₁s of the two acquired IR sequences. The drSIR sequence is also very sensitive to reductions in T₁ produced by Gadolinium based contrast agents (GBCAs), and when used with rigid body registration to align three-dimensional (3D) isotropic pre and post GBCA images may be of considerable value in showing subtle GBCA enhancement. In serial MRI studies performed at different times, the high signal boundaries generated by dSIR and drSIR sequences can be used with rigid body registration of 3D isotropic images to demonstrate contrast arising from small changes in T₁ (without or with GBCA enhancement) as well as small changes in the spatial properties of normal tissues and lesions, such as their site, shape, size and surface. Applications of the sequences in cases of multiple sclerosis (MS) and methamphetamine dependency are illustrated. Using targeted narrow mD dSIR sequences, widespread abnormalities were seen in areas of normal appearing white matter shown with conventional T₂-wSE and T₂-FLAIR sequences. Understanding of the features of dSIR and drSIR images is facilitated by the use of their T₁-bipolar filters; to explain their targeting, signal, contrast, boundaries, T₁ mapping and GBCA enhancement. Targeted MRI (tMRI) using dSIR and drSIR sequences may substantially improve clinical MRI of the brain by providing unequivocal demonstration of abnormalities that are not seen with conventional sequences.

Review Article Improving the understanding and performance of clinical MRI using tissue property filters and the central contrast theorem, MASDIR pulse sequences and synergistic contrast MRI Ya-Jun Ma, Dina Moazamian, Daniel M. Cornfeld, Paul Condron, Samantha J. Holdsworth, Mark Bydder, Jiang Du, Graeme M. Bydder

This paper describes a quantitative approach to understanding the signal, contrast and weighting of magnetic resonance (MR) images. It uses the concept of pulse sequences as tissue property (TP) filters and models the signal, contrast and weighting of sequences using either a single TP-filter (univariate model) or several TP-filters (the multivariate model). For the spin echo (SE) sequence using the Bloch equations, voxel signal intensity is plotted against the logarithm of the value of the TPs contributing to the sequence signal to produce three TP-filters, an exponential ρ_m-filter, a low pass T₁-filter and a high pass T₂-filter. Using the univariate model which considers signal changes in only one of ρ_m, T₁, or T₂ at a time, the first partial derivative of signal with respect to the natural logarithm of ρ_m, T₁ or T₂ is the sequence weighting for each filter (for small changes in each TP). Absolute contrast is then the sequence weighting multiplied by the fractional change in TP for each filter. For large changes in TPs, the same approach is followed, but using the mean slope of the filter as the sequence weighting. These approaches can also be used for fractional contrast. The univariate TP-filter model provides a mathematical framework for converting conventional qualitative univariate weighting as used in everyday clinical practice into quantitative univariate weighting. Using the multivariate model which considers several TP-filters together, the relative contributions of each TP to overall sequence and image weighting are expressed as sequence and imaging weighting ratios respectively. This is not possible with conventional qualitative weighting which is univariate. The same approaches are used for inversion recovery (IR), pulsed gradient SE, spoiled gradient echo (SGE), balanced steady state free precession, ultrashort echo time and other pulse sequences. Other TPs such as susceptibility, chemical shift and flow can be included with phase along the Y axis of the TP-filter. Contrast agent effects are also included. In the text TP-filters are distinguished from k-space filters, signal filters (S-filters) which are used in imaging processing as well as to describe windowing the signal width and level of images, and spatial filters. The TP-filters approach resolves many of the ambiguities and inconsistencies associated with conventional qualitative weighting and provides a variety of new insights into the signal, contrast and weighting of MR images which are not apparent using qualitative weighting. The TP-filter approach relates the preparation component of pulse sequences to voxel signal, and contrast between two voxels. This is complementary to k-space which relates the acquisition component of pulse sequences to the spatial properties of MR images and their global contrast.

Divided and subtracted MRI is a novel imaging processing technique, where the difference of two images is divided by their sum. When the sequence parameters are chosen properly, this results in images with a high T₁ or T₂ weighting over a small range of tissues with specific T₁ and T₂ values. In the T₁ domain, we describe the implementation of the divided Subtracted Inversion Recovery Sequence (dSIR), which is used to image very small changes in T₁ from normal in white matter. dSIR has shown widespread changes in otherwise normal-appearing white matter in patients suffering from mild traumatic brain injury (mTBI), substance abuse, and ischemic leukoencephalopathy. It can also be targeted to measure small changes in T₁ from normal in other tissues. In the T₂ domain, we describe the divided echo subtraction (dES) sequence that is used to image musculoskeletal tissues with a very short T₂*. These tissues include fascia, tendons, and aponeuroses. In this manuscript, we explain how this contrast is generated, review how these techniques are used in our research, and discuss the current challenges and limitations of this technique.

This paper reviews magnetic resonance (MR) pulse sequences in which the same or different tissue properties (TPs) such as T₁ and T₂ are used to contribute synergistically to lesion contrast. It also shows how synergistic contrast can be created with Multiplied, Added, Subtracted and/or fiTted Inversion Recovery (MASTIR) sequences, and be used to improve the sensitivity, specificity and scope of clinical magnetic resonance imaging (MRI) protocols. Synergistic contrast can be created from: (i) the same TP, e.g., T₁ used twice or more in a pulse sequence; (ii) different TPs such as ρ_m, T₁, T₂, and D* used once or more within a sequence, and (iii) additional suppression or reduction of signals from tissues and/or fluids such as fat, long T₂ tissues and cerebrospinal fluid (CSF). The short inversion time (TI) inversion recovery (IR) (STIR) and double IR (DIR) sequences usually show synergistic positive contrast for lesions which have increases in both T₁ and T₂. The diffusion weighted pulsed gradient spin echo (PGSE) sequence shows synergistic contrast for lesions which have an increase in T₂ and a decrease in D*; the sequence is both positively weighted for T₂ and negatively weighted for D*. In the brain, when an IR sequence nulling white matter has subtracted from it an IR sequence nulling gray matter to form the subtracted IR (SIR) sequence, increases in the single TP T₁ between the two nulling points of the original two sequences generate high synergistic positive contrast. In addition, the subtraction to produce the SIR sequence reduces fat and CSF signals. To provide high sensitivity to changes in TPs in disease the SIR sequence can be used (i) alone to provide synergistic T₁ contrast as above; (ii) with T₂-weighting to provide synergistic T₁ and T₂ contrast, and (iii) with T₂- and D*-weighting to provide synergistic T₁, T₂, and D* contrast. The SIR sequence can also be used in reversed form (longer TI form minus shorter TI form) to produce very high positive synergistic T₁ contrast for reductions in T₁, and so increase the positive contrast enhancement produced by clinical gadolinium-based contrast agents (GBCAs) when they reduce T₁. The specificity of MRI examinations can be improved by using the reversed SIR sequence with a long echo time (TE) gradient echo as well as echo subtraction to show synergistic high contrast from T₁ and T₂* shortening produced by organic iron. Other added and subtracted forms of the MASTIR sequence can be used synergistically to selectively show myelin, myelin water and fluids including blood and CSF. Protocols using MASTIR sequences to provide synergistic contrast in MRI of the brain, prostate and articular cartilage are included as illustrative examples, and the features of synergistic contrast MRI (scMRI) are compared to those of multiparametric MRI (mpMRI) and functional MRI (fMRI).

Ultra-high contrast (UHC) MRI describes forms of MRI in which little or no contrast is seen on conventional MRI images but very high contrast is seen with UHC techniques. One of these techniques uses the divided subtracted inversion recovery (dSIR) sequence, which, in modelling studies, can produce ten times the contrast of conventional inversion recovery (IR) sequences. When used in cases of mild traumatic brain injury (mTBI), the dSIR sequence frequently shows extensive abnormalities in white matter that appears normal when imaged with conventional T₂-fluid-attenuated IR (T₂-FLAIR) sequences. The changes are bilateral and symmetrical in white matter of the cerebral and cerebellar hemispheres. They partially spare the anterior and posterior central corpus callosum and peripheral white matter of the cerebral hemispheres and are described as the whiteout sign. In addition to mTBI, the whiteout sign has also been seen in methamphetamine use disorder and Grinker’s myelinopathy (delayed post-hypoxic leukoencephalopathy) in the absence of abnormalities on T₂-FLAIR images, and is a central component of post-insult leukoencephalopathy syndromes. This paper describes the concept of ultra-high contrast MRI, the whiteout sign, the theory underlying the use of dSIR sequences and post-insult leukoencephalopathy syndromes.