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Amplified MRI (aMRI) is a promising new technique that can visualize pulsatile brain tissue motion by amplifying sub-voxel motion in cine MRI data, but it lacks the ability to quantify the sub-voxel motion field in physical units. Here, we introduce a novel post-processing algorithm called 3D quantitative amplified MRI (3D q-aMRI). This algorithm enables the visualization and quantification of pulsatile brain motion. 3D q-aMRI was validated and optimized on a 3D digital phantom and was applied in vivo on healthy volunteers for its ability to accurately measure brain parenchyma and CSF voxel displacement. Simulation results show that 3D q-aMRI can accurately quantify sub-voxel motions in the order of 0.01 of a voxel size. The algorithm hyperparameters were optimized and tested on in vivo data. The repeatability and reproducibility of 3D q-aMRI were shown on six healthy volunteers. The voxel displacement field extracted by 3D q-aMRI is highly correlated with the displacement measurements estimated by phase contrast (PC) MRI. In addition, the voxel displacement profile through the cerebral aqueduct resembled the CSF flow profile reported in previous literature. Differences in brain motion was observed in patients with dementia compared with age-matched healthy controls. In summary, 3D q-aMRI is a promising new technique that can both visualize and quantify pulsatile brain motion. Its ability to accurately quantify sub-voxel motion in physical units holds potential for the assessment of pulsatile brain motion as well as the indirect assessment of CSF homeostasis. While further research is warranted, 3D q-aMRI may provide important diagnostic information for neurological disorders such as Alzheimer's disease.

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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.

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Chiari type 1 malformation is a neurological disorder characterized by an obstruction of the cerebrospinal fluid (CSF) circulation between the brain (intracranial) and spinal cord (spinal) compartments. Actions such as coughing might evoke spinal cord complications in patients with Chiari type 1 malformation, but the underlying mechanisms are not well understood. More insight into the impact of the obstruction on local and overall CSF dynamics can help reveal these mechanisms. Therefore, our previously developed computational fluid dynamics framework was used to establish a subject-specific model of the intracranial and upper spinal CSF space of a healthy control. In this model, we emulated a single cough and introduced porous zones to model a posterior (OBS-1), mild (OBS-2), and severe posterior-anterior (OBS-3) obstruction. OBS-1 and OBS-2 induced minor changes to the overall CSF pressures, while OBS-3 caused significantly larger changes with a decoupling between the intracranial and spinal compartment. Coughing led to a peak in overall CSF pressure. During this peak, pressure differences between the lateral ventricles and the spinal compartment were locally amplified for all degrees of obstruction. These results emphasize the effects of coughing and indicate that severe levels of obstruction lead to distinct changes in intracranial pressure.

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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.

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Background: Delayed Post-Hypoxic Leukoencephalopathy (DPHL), or Grinker's myelinopathy, is a syndrome in which extensive changes are seen in the white matter of the cerebral hemispheres with MRI weeks or months after a hypoxic episode. T2-weighted spin echo (T2-wSE) and/or T2-Fluid Attenuated Inversion Recovery (T2-FLAIR) images classically show diffuse hyperintensities in white matter which are thought to be near pathognomonic of the condition. The clinical features include Parkinsonism and akinetic mutism. DPHL is generally regarded as a rare condition. Methods and Results: Two cases of DPHL imaged with MRI nine months and two years after probable hypoxic episodes are described. No abnormalities were seen on the T2-FLAIR images with MRI, but very extensive changes were seen in the white matter of the cerebral and cerebellar hemisphere on divided Subtraction Inversion Recovery (dSIR) images. dSIR sequences may produce ten times the contrast of conventional inversion recovery (IR) sequences from small changes in T1. The clinical findings in both cases were of cognitive impairment without Parkinsonism or akinetic mutism. Conclusion: The classic features of DPHL may only represent the severe end of a spectrum of diseases in white matter following global hypoxic injury to the brain. The condition may be much more common than is generally thought but may not be recognized using conventional clinical and MRI criteria for diagnosis. Reappraisal of the syndrome of DPHL to include clinically less severe cases and to encompass recent advances in MRI is advocated.

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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.

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Our study methodology is motivated from three disparate needs: one, imaging studies have existed in silo and study organs but not across organ systems; two, there are gaps in our understanding of paediatric structure and function; three, lack of representative data in New Zealand. Our research aims to address these issues in part, through the combination of magnetic resonance imaging, advanced image processing algorithms and computational modelling. Our study demonstrated the need to take an organ-system approach and scan multiple organs on the same child. We have pilot tested an imaging protocol to be minimally disruptive to the children and demonstrated state-of-the-art image processing and personalized computational models using the imaging data. Our imaging protocol spans brain, lungs, heart, muscle, bones, abdominal and vascular systems. Our initial set of results demonstrated child-specific measurements on one dataset. This work is novel and interesting as we have run multiple computational physiology workflows to generate personalized computational models. Our proposed work is the first step towards achieving the integration of imaging and modelling improving our understanding of the human body in paediatric health and disease.

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This paper updates and extends three previous papers on tissue property filters (TP-filters), Multiplied, Added, Divided and/or Subtracted Inversion Recovery (MASTIR) pulse sequences and synergistic contrast MRI (scMRI). It does this by firstly adding the central contrast theorem (CCT) to TP-filters, secondly including division with MASTIR sequences to make them Multiplied, Added, Subtracted and/or Divided IR (MASDIR) sequences, and thirdly incorporating division into the image processing needed for scMR to increase synergistic T1 contrast. These updated concepts are then used to explain and improve contrast at tissue boundaries, as well as to develop imaging regimes to detect and monitor small changes to the brain over time and quantify T1. The CCT is in two parts: the first part states that contrast produced by each TP is the product of the change in TP multiplied by the TP sequence weighting which is the first partial derivative of the TP-filter. The second part states that the overall fractional contrast is the algebraic sum of the fractional contrasts produced by each of the TPs. Subtraction of two IR sequences alone about doubles contrast relative to a conventional single IR sequence. Division of this subtraction can amplify contrast 5-15 times compared with conventional IR sequences. Dividing sequences can be problematic in areas where the signal is zero but this is avoided by dividing the difference in signal of two magnitude reconstructed IR sequences by the sum of their signals. The basis for the production of high contrast, high spatial resolution boundaries at white-gray matter junctions, between cerebral cortex and cerebrospinal fluid (CSF) and at other sites with subtracted IR (SIR) and divided subtracted IR (dSIR) sequences is explained and examples are shown. A key concept is the tissue fraction f, which is the proportion of a tissue in a mixture of two tissues within a voxel. Contrast at boundaries is a function of the partial derivative of the TP-filter, the partial derivative of the relevant TP with respect to f, and the partial derivative of f with respect to distance, x. Location of tissue boundaries is important for segmentation and is helpful in determining if inversion times have been chosen correctly. In small change regimes, the high sensitivity to small changes in T1 provided by dSIR images, together with the high definition boundaries, afford mechanisms for detecting small changes due to contrast agents, disease, perfusion and other causes. 3D isotropic rigid body registration provides a technique for following these changes over time in serial studies. Images showing high lesion contrast, high definition tissue and fluid boundaries, and the detection of small changes are included. T1 maps can be created by linearly scaling dSIR images.