Graeme M. Bydder

Ultra-high contrast (UHC) magnetic resonance imaging (MRI) is a term used to describe magnetic resonance (MR) imaging that shows abnormalities with high contrast when little or no abnormality is seen on common conventional state-of-the-art MR images. It is achieved without the use of increased static or gradient magnetic fields. UHC can be accomplished by using tissue properties such as T₁ and T₂ twice or more in the same sequence. This synergistically contributes to overall contrast as with directly acquired divided subtracted inversion recovery (dSIR) T₁-BipoLAr Inversion Recovery (BLAIR) sequences. These sequences can also provide high contrast and high spatial resolution signal boundaries. UHC MRI can also be achieved by applying synthetic bipolar filters to high quality tissue property maps. Illustrative cases of mild traumatic brain injury (mTBI), multiple sclerosis (MS), methamphetamine substance use disorder, Parkinson’s disease and white matter changes associated with a cerebral tumour are shown. Patients showed widespread abnormalities with directly acquired and synthetic dSIR and other BLAIR images in areas where little or no abnormality was seen on conventional T₂-w spin echo and/or T₂-FLAIR images. New signs seen on BLAIR images include the whiteout sign and grayout signs as well as the bilaminar cortex and bubble signs. dSIR and other BLAIR sequences create high contrast from small changes in T₁ as well as other tissue properties, and are complementary to conventional clinical sequences which create high contrast from larger changes in T₁ and/or T₂. Comparison is made with other sequences which use single or combined inversion recovery images. Four groups of BLAIR sequences are described. They utilise sequences that already exist on most MR machines and are easy to implement.

Background Management of patients with persistent or worsening symptoms following traumatic brain injury (TBI) presents difficulties. MRI is usually negative in mild TBI (mTBI) and usually only shows residual quiescent disease in moderate to severe TBI (msTBI). Objective We hypothesize that patients with persistent symptoms from prior TBI will show findings on a divided Subtracted Inversion Recovery (dSIR) sequence that are sensitive to small changes from normal in white matter T₁. Materials and methods Neurologically healthy controls (n = 37) and patients with persistent symptoms following TBI (n = 29) were examined with T₂-FLAIR and dSIR sequences. T₂-FLAIR images were evaluated for minor changes and overt pathology. dSIR images were evaluated for “whiteout signs” defined as widespread, bilateral, and symmetrical high signal in white matter. Odds ratios were calculated for the association between the presence of a whiteout sign and being in the symptomatic group. Results Overt pathology was seen on the T₂-FLAIR images in six msTBI patients and one mTBI patient. No widespread changes were seen on the T₂-FLAIR images in the control or TBI groups. Whiteout signs were seen on the dSIR images in 25 of 29 TBI patients and in three of 37 controls. The whiteout sign was strongly associated with symptomatic TBI status, with odds ratios ≥ 14. The kappa statistic for inter-reader correlation (whiteout sign vs. no whiteout sign) was κ = 0.85. Conclusion The whiteout sign was strongly associated with being in the symptomatic group and is a potential biomarker for recognition of secondary changes to the brain in patients with persistent symptoms following TBI.

Ultra-high contrast (UHC) MRI is a term used to describe MR imaging that shows abnormalities with high contrast when little or no abnormality is seen on common conventional state-of-the-art MR images. It is achieved without the use of increased static or gradient magnetic fields. UHC can be accomplished by using tissue properties such as T1 and T2 twice or more in the same sequence. This synergistically contributes to overall contrast as with directly acquired divided subtracted inversion recovery (dSIR) T1-BipoLAr Inversion Recovery (BLAIR) sequences. These sequences can also provide high contrast and high spatial resolution signal boundaries. UHC MRI can also be achieved by applying synthetic bipolar filters to high quality tissue property maps. Illustrative cases of mild traumatic brain injury, multiple sclerosis, methamphetamine substance use disorder, Parkinson's disease and white matter changes associated with a cerebral tumour are shown. Patients showed widespread abnormalities with directly acquired and synthetic dSIR and other BLAIR images in areas where little or no abnormality was seen on conventional T2-w spin echo and/or T2-FLAIR images. New signs seen on BLAIR images include the whiteout sign and grayout signs as well as the bilaminar cortex and bubble signs. dSIR and other BLAIR sequences create high contrast from small changes in T1 as well as other tissue properties, and are complementary to conventional clinical sequences which create high contrast from larger changes in T1 and/or T2. Comparison is made with other sequences which use single or combined inversion recovery images. Four types of BLAIR sequences are described. They utilise sequences that already exist on most MR machines and are easy to implement.

Recent interest in musculoskeletal connective tissues like tendons, aponeurosis, and deep fascia has led to a greater focus on in vivo medical imaging, particularly MRI. Given the rapid T₂* decay of collagenous tissues, advanced ultra-short echo time (UTE) MRI sequences have proven useful in generating high-signal images of these tissues. To further these advances, we discuss the integration of UTE with Diffusion Tensor Imaging (DTI) and explore image processing techniques to enhance the localization, labeling, and modeling of connective tissues. These techniques are especially valuable for extracting features from thin tissues that may be difficult to distinguish. We present data from lower leg scans of 30 healthy subjects using a non-Cartesian MRI sequence to acquire axial 2D images to segment skeletal muscle and connective tissue. DTI helped differentiate aponeurosis from deep fascia by analyzing muscle fiber orientations. The dual echo imaging methods yielded high-resolution images of deep fascia, where in-plane spatial resolutions were between 0.3 × 0.3 mm to 0.5 × 0.5 mm with a slice thickness of 3–5 mm. Techniques such as K-Means clustering, FFT edge detection, and region-specific scaling were most effective in enhancing images of deep fascia, aponeurosis, and tendon to enable high-fidelity modeling of these tissues.

In this educational review, the basic physics underlying the use of ultra-high contrast (UHC) bipolar filter (BLAIR) sequences, including divided subtracted inversion recovery (dSIR), is explained. These sequences can increase the contrast produced by small changes in T₁ by a factor of ten or more compared with conventional IR sequences. In illustrative cases, the sequences were used in multiple sclerosis (MS) patients during relapse and remission and were compared with positionally matched conventional (T₂-weighted spin echo, T₂-FLAIR) images. Well-defined focal lesions were seen with dSIR sequences in areas where little or no change was seen with conventional sequences. In addition, widespread abnormalities affecting almost all of the white matter of the brain were seen during relapses when there were no corresponding abnormalities seen on conventional sequences (the whiteout sign). Grayout signs, in which there is a loss of contrast in gray matter or between gray matter and CSF, were also seen, as well as high signal boundaries around lesions. Disruption of the usual high signal boundary between white and gray matter was seen in leucocortical lesions. Lesions in the spinal cord were better seen or only seen with dSIR sequences. Generalized change was observed in the optic nerve with the dSIR sequence in a case of optic neuritis. UHC BLAIR sequences may be of considerable value for recognition of abnormalities in clinical practice and in research studies on MS.

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.

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.

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.

In modelling studies targeted MRI (tMRI) of small increases in the T1 of tissues using divided Subtracted Inversion Recovery (dSIR) sequences show ten or more times the contrast seen with conventional IR sequences. This may be particularly useful in imaging normal appearing white matter where there may be small changes in T1 and/or T2 in disease but these changes may be insufficient to produce useful contrast with conventional T2-weighted spin echo (T2-wSE) and T2-FLuid Attenuated Inversion Recovery (T2-FLAIR) sequences. In a case of recurrent mild Traumatic Brain Injury (mTBI), very extensive high contrast abnormalities were seen in white matter using a dSIR sequence that targeted small increases in T1 in areas where no abnormality was apparent with T2-wSE or T2-FLAIR sequences. The increases in T1 may be due to neuroinflammation and/or degeneration which produces the abnormalities seen on the dSIR images. tMRI of normal appearing white matter may have widespread application in clinical MRI of the brain.