Ультра-высокий контраст (УХК) MRI изображений мозгового, спинного и оптического нерва в множестве склероза с использованием непосредственно приобретенного и синтетического биполярного фильтра (BLAIR).

1. Introduction

Ultra-high contrast (UHC) MRI is a term used to describe MRI which shows high-contrast demonstration of abnormalities in situations where little or no change from normal is seen on conventional state-of-the-art MR images. It is achieved without increase in static or gradient field strength.

With conventional MR sequences, change in a tissue property such as T 1 is usually used only once to create contrast. With one form of UHC MRI, the same change in a tissue property is used three or four times in the same sequence to create much greater contrast [ 1 ]. An example of this is the divided subtracted inversion recovery (dSIR) sequence, where changes in T 1 are used repeatedly to increase contrast. The contrast from small changes in T 1 with dSIR sequences may be ten or more times greater than that obtained with conventional IR sequences such as MP-RAGE (magnetization prepared-rapid acquisition gradient echo). Using this approach, widespread changes have been seen in mild traumatic brain injury (mTBI) and hypoxic injury to the brain in regions which show no abnormality with state-of-the-art T 2 -weighted spin echo (T 2 -wSE) and/or T 2 -weighted fluid attenuated inversion recovery (T 2 -FLAIR) sequences [ 2 , 3 , 4 ]. This is likely to be because the changes in tissue properties such as T 1 and T 2 are too small to show abnormalities with conventional sequences, but produce obvious changes with the greater contrast amplification provided by dSIR sequences.

There is little point in demonstrating lesions that are already seen with high contrast using conventional sequences with even greater contrast, so the focus in applications of UHC MRI has been on areas of the brain that show little or no lesion contrast and appear normal with conventional sequences [ 5 ].

In an earlier paper, a single case of multiple sclerosis (MS) was described in order to demonstrate the technical capabilities of a dSIR sequence [ 1 ]. In this paper, we demonstrate more cases of MS imaged with dSIR sequences, as well as a new bipolar filter sequence, namely, log then subtracted inversion recovery (lSIR). The paper also illustrates how the T 1 -dependent dSIR and lSIR sequences can be supplemented by other tissue properties such as T 2 in the form of composite bipolar filter sequences. MS patients were examined in remission and during relapse.

In the next section of this educational review, the basic physics underlying the use of bipolar sequences is described. This is followed by a comparison of conventional and bipolar sequences to determine where the new sequences are likely to be of clinical or research value.

2. Basic Physics

The first part of this section is a condensed and updated version of work published previously [ 1 , 5 ]. The second part describes new techniques.

2.1. Tissue Property Filters (TP-Filters) and the Inversion Recovery (IR) Sequence

Instead of illustrating image contrast in the usual way, by plotting longitudinal and then transverse magnetization (M Z and then M XY ) against time using the Bloch equations, it is possible to use plots of signals against T 1 and T 2 , respectively. These plots are tissue property filters (TP-filters); the TPs may be mobile proton density, T 1 , T 2 , T 2 *, D*, etc.

For TR >> T 1 , the T 1 dependent part of the IR sequence has the following signal equation:

where S T1 is the signal from the T 1 -filter, TI in the inversion time, and T 1 is the longitudinal magnetization relaxation time. Two T 1 -filters of the IR sequence with different values of TI (TI s = TI short and TI i = TI intermediate ) are shown in magnitude form in Figure 1 A. The curves are negative unipolar filters.

Unipolar IR ( A ), subtracted IR (SIR) ( B ), and Added IR (AIR) ( C ) T 1 -filters. T 1 is shown along the X axes in ms. ( A ) shows a TI s T 1 -unipolar filter (pink) and a TI i T 1 -unipolar filter (blue), ( B ) shows the subtraction (S TIs − S TIi ) IR or SIR T 1 -bipolar filter, and ( C ) shows the addition (S TIs + S TIi ) IR or AIR T 1 -filter. The vertical dashed lines divide the X axes into lD, mD, and hD segments with the mD central. In ( B ), the slope of the curve in the mD of the SIR T 1 -filter is about double that of the S TIs T 1 -filter (pink in [ A ]). In ( C ), the signal at T 1 = 0 is doubled to 2.0, and the signal in the mD is about 0.20 in the central part of the AIR T 1 -filter (i.e., in the mD).

The subtraction is as follows: first, TI s T 1 -unipolar filter minus the second TI i T 1 -unipolar filter produces the subtracted IR (SIR) T 1 -bipolar filter seen in Figure 1 B. The vertical dashed lines at the null points of the two IR T 1 -filters seen in Figure 1 divide the X axes in Figure 1 B,C into the lowest Domain (lD), the middle Domain (mD), and the highest Domain (hD). In the mD in Figure 1 B (between the two dashed lines), the size of the slope of the SIR T 1 -bipolar filter is about double that of the IR T 1 -unipolar filters in the mD shown in Figure 1 A. This is because the slope of the SIR filter in its mD in Figure 1 B is the positive slope of the TI s filter in the mD shown in Figure 1 A minus the negative slope of the TI i filter in the mD also shown in Figure 1 A.

The two IR T 1 -filters shown in Figure 1 A can also be added to give the Added IR (AIR) T 1 -filter shown in Figure 1 C. In its mD, which is bounded by the vertical dashed lines, the signal is reduced to about 0.20 compared with its value of 2 at T 1 = 0 (i.e., about one tenth of the value).

Figure 2 A shows a divided SIR (dSIR) T 1 -bipolar filter in which the SIR T 1 -bipolar filter in Figure 1 B is divided by the AIR T 1 -filter in Figure 1 C, i.e., difference sum . The signal S dSIR of the dSIR filter is given by the following:

where S TIs is the signal from the shorter TI filter and S TIi is the signal from the intermediate TI i filter.

( A ) shows division of the SIR T 1 -bipolar filter ( Figure 1 B) by the addition AIR T 1 -filter ( Figure 1 C) to give the dSIR T 1 -bipolar filter. ( B ) shows comparison of a conventional IR S TIs T 1 -unipolar filter (pink) with the SIR T 1 -bipolar filter (blue) for a small increase in T 1 (ΔT1) (horizontal green arrow). ΔTI is multiplied by the slopes of the filters to give the differences in signal or contrast, ΔS. The dSIR T1-bipolar filter produces about twice the contrast of the STIs T1-unipolar filter for the SIR filter (blue and pink arrows). ( C ) compares the S TIs T 1 -unipolar filter (pink) with the dSIR T 1 -bipolar filter (blue) for the same small increase in T 1. The dSIR T 1 -bipolar filter produces about ten times more contrast than the S TIs T 1 -unipolar filter (blue and pink arrows).

The resulting dSIR T 1 -bipolar filter ( Figure 2 A) shows a negative pole and a positive pole. Its mD shows a highly positive nearly linear slope whose magnitude is about ten times greater than the slopes of the IR T 1 -filters shown in Figure 1 A. The dSIR filter has maximum and minimum signal values of ±1. (The contributions from mobile proton density and T 2 to conventional IR sequences cancel out with dSIR sequences, which are, therefore, T 1 maps. As a result, the whole sequence can be accurately represented by its T 1 -bipolar filter.)

Figure 2 B compares the contrast generated by a conventional S TIs IR T 1 -unipolar filter (pink) to that from the SIR T 1 -bipolar filter (blue) shown in Figure 1 B, from the same increase in T 1 (ΔT 1 ) (horizontal positive green arrow). Using the small change approximation of differential calculus, ΔT 1 is multiplied by the slopes of the respective S TI IR and SIR filters (red lines) to produce the differences in signal ΔS shown, i.e., the contrast resulting from each of them. This is given by the vertical pink and blue arrows on the right. The SIR T 1 -bipolar filter generates about twice the contrast (blue arrow) of the S TIs IR T 1 -unipolar filter (pink arrow) from the same increase in T 1 , ΔT 1 . The S TIs IR T 1 -filter is that of a conventional IR sequence such as MP-RAGE.

Figure 2 C compares the contrast produced by the S TIs IR T 1 -unipolar filter (pink) to that produced by the dSIR T 1 -bipolar filter shown in Figure 2 A (blue). The increase in T 1 ΔT 1 (horizontal positive green arrow) is multiplied by the slopes of the respective S TIs IR and dSIR filters (red lines) to produce the differences in signal ΔS shown, i.e., the contrast generated by the two filters. This is given by the vertical pink and blue arrows on the right. From the same increase in T 1 (ΔT 1 ), the dSIR T 1 -bipolar filter produces contrast about ten times greater than the contrast produced by the S TIs IR T 1 -unipolar filter.

To produce the large increase in contrast shown in Figure 2 C, the dSIR sequence is typically targeted at small increases in the T 1 of normal tissue produced by disease (shown by the horizontal green arrow). These increases are positioned within the steeply sloping mD of the dSIR T 1 -bipolar filter. This is achieved by choosing appropriate values of TI s and TI i . The target is often small increases in the T 1 of white matter.

High contrast can also be produced by difference or change in T 1 within the lower part of the hD and the upper part of the lD, where the dSIR T 1 -bipolar filter has relatively steep slopes. (The term ‘tissue’ is used to include fluids in the rest of this paper unless otherwise specified).

2.2. Contrast at Tissue Boundaries

MRI tissue boundaries take different forms, such as a gradual change in signal from one tissue to another, as well as sharply defined high and low signal boundaries between tissues.

In the boundary region between two pure tissues (such as between white and gray matter), the T 1 s of voxels which contain mixtures of the two tissues typically span the range of T 1 values between those of the two pure tissues. If a narrow mD dSIR T 1 -bipolar filter (e.g., with TI s nulling normal white matter and TI i longer than TI s but less than that needed to null gray matter) is used, there are mixtures of the two tissues in voxels in the boundary region, with intermediate T 1 values (T 1W,G ) which correspond with the peak signal of the T 1 -bipolar filter (S W,G ), as shown in Figure 3 (vertical blue arrow). This produces a high signal boundary between white matter and gray matter. The dSIR T 1 -bipolar filter shows much higher contrast than that produced between white matter and gray matter by a conventional white matter nulled IR sequence such as MP-RAGE ( Figure 3 ) (vertical pink arrow). High contrast boundaries are also seen at the junction between white matter and CSF at ventricular boundaries through the same mechanism.

Contrast at tissue boundaries. This image shows a narrow mD dSIR T 1 -bipolar filter with a mD extending from the T 1 of white matter (W) to a T 1W,G between the TIs of W and gray matter (G) (blue curve), as well as a white-matter-nulled conventional IR T 1 -unipolar filter e.g., MP-RAGE (pink curve). The X axis is shown in ms. The contrast produced by the T 1 -unipolar filter from the difference in signal between W and G is (S G minus S W ) and is shown by the vertical pink arrow. With the dSIR T 1 -bipolar filter, there is a partial volume effect between W and G, producing a T 1W,G between the T 1 s of W and G, which results in the high signal S W,G shown on the T 1 -bipolar filter (blue curve). The contrast between this high signal and white matter is the difference (S W,G minus S W , in blue) and is shown by the vertical blue arrow. The contrast produced by the T 1 -bipolar filter at the boundary between W and G is far greater than that produced at the boundary between W and G by the T 1 -unipolar filter.

2.3. T 1 Maps and Qualitative—Quantitative MRI

To better understand the dSIR T 1 -bipolar filter, a linear equation of the form y = mx + c can be used to approximate the filter in its mD. The equation is produced by fitting a straight line between the first and last points of the mD (i.e., first point x = TI s ln 2 and y = −1, and last point x = TI i ln 2 and y = +1). In the mD, the signal of the dSIR sequence S dSIR , is given by the following:

where ΔTI = TI i − TI s (i.e., second TI minus first TI), which is positive, and ΣTI = TI s + TI i , which is also positive. Note that, because ΔTI is positive, the slope ln   4 ∆ T I is positive. The offset is negative. T 1 is the longitudinal magnetization relaxation time.

The expression in Equation (3) illustrates four key features of the dSIR T 1 -bipolar filter, firstly, the near linear change in signal (i.e., S dSIR ) with T 1 in the mD, secondly, the filter has a slope in the mD equal to ln 4 Δ TI , thirdly, the filter shows a high sensitivity to small changes in T 1 when the size of ΔTI is small. When ΔT 1 is small, the size of ΔTI can be decreased to match it, and so the sensitivity of the filter is scaled up. This is because the reduction in ΔTI increases the steepness of the T 1 -filter in the mD and, thus, the amplification of the contrast produced from ΔT 1 . It compensates for the small value of ΔT 1 until the sequence becomes SNR and/or artefact limited. This is not the case with conventional IR sequences, where, if ΔT 1 is decreased, contrast is decreased.

Fourthly, Equation (3) can be used to calculate T 1 values in the mD, as follows:

The terminology is the same as for Equation (3).

The linear approximation is only valid in the mD.

T 1 s in the mD occupy the full range of the display gray scale from black to white. Outside of the mD, in the lD and hD, the magnitude of the T 1 -bipolar filter signal decreases towards zero at minimum and maximum values of T 1 . T 1 s, from the shortest and longest T 1 s in the lD and hD, respectively, only occupy parts of the display gray scale.

2.4. Log then Subtracted Inversion Recovery (lSIR) Sequences

Another bipolar filter is the natural logarithm (ln) then subtracted inversion recovery (lSIR) filter. This is half of the following subtraction: ln short S TIs minus ln intermediate S TIi . Figure 4 shows a dSIR T 1 -bipolar filter in blue and the corresponding lSIR T 1 -bipolar filter with the same TI s and TI i in orange. The two filters appear similar in the lowest region of the lD and in the highest region of the hD, as well as in the central region of the mD. The slope of the dSIR filter (blue) in the mD is essentially constant and equal to ln 4 Δ TI . The slope of the lSIR filter (orange) is the same as that of the dSIR filter at the center of the mD, but greater around the lower and higher nulling TI values. The signal of the lSIR filter asymptotically approaches negative and positive infinity at the two corresponding nulling T 1 s. The lSIR filter increases its slope, and, thus, its contrast amplification, as the change in T 1 from the nulling value of T 1 becomes smaller. This compensates for the decrease in the size of the change in T 1 . The low and high signal peaks of the lSIR filter are narrower than those of the corresponding dSIR filter, which results in narrower boundaries between white and gray matter.

Plot of signal vs. T 1 in ms for a dSIR T 1 -bipolar filter (blue curve) and the corresponding lSIR T 1 -bipolar filter with the same nulling points (orange curve). The dSIR filter shows the pattern seen in Figure 2 and Figure 3 with maximum values of ±1. The lSIR filter has similar values to dSIR filter in the regions of lowest and highest values of T 1 , as well as in the center of the mD. However, around the lower and upper T 1 nulling values it is much steeper and proceeds asymptotically to minus and plus infinity respectively (values along the Y axis in the range of ± 2 are shown). For the same difference in T 1 in boundary regions, the lSIR filter is steeper than the dSIR filter. This results in greater contrast. The contrast for very small differences or changes in T 1 is typically about 2–3 times greater with the lSIR sequence compared with the corresponding dSIR sequence.

Like the dSIR filter, the lSIR filter essentially eliminates the mobile proton density and T 2 dependence of the full IR sequence and so can be used to model the contrast behavior of the full IR sequence.

From a practical point of view, the lSIR T 1 -filter has 2–3 times the slope of the dSIR T 1 -filter for very small differences or changes in T 1 around the null points, and, thus, has a 20–30 times greater contrast than conventional IR sequences for the same very small differences or changes in T 1 . The maximum and minimum values of the lSIR filter are usually shown as ±2–3 (rather than ±infinity). This compares with values of ±1 for the dSIR filter.

The lSIR filter signal, S lSIR , is the inverse hyperbolic tangent of the dSIR filter signal, S dSIR , in the mD (S lSIR = atanh S dSIR ) and the inverse hyperbolic cotangent of the dSIR filter signal in the lD and hD.

2.5. Composite (c) Bipolar Filters (T 1 as well as T 2 , T 2 *, and/or D*)

It is possible to introduce an attenuation filter S OF (S other filter ) in the form of an additional segment of the IR pulse sequence and apply it to one of the two IR sequences used for dSIR T 1 -bipolar filter imaging in Figure 1 and Figure 2 . S OF may equal e −ΔTE/T2 , e −ΔTE/T2* , or e −ΔbD* (where ΔTE and Δb are the differences in TE or b [the diffusion sensitivity parameter] between the two IR sequences). This, respectively, introduces T 2 , T 2 *, and D* dependence. It provides additional contrast to the T 1 contrast of the dSIR T 1 -bipolar filter. When ΔTE equals zero, or Δb equals zero, S OF = 1 and there is no attenuation. If S OF is set to 1.0, 0.5, and 0.25, the curves shown in Figure 5 A,B result when using a narrow mD dSIR sequence (TI s = 350 ms and TI i = 500 ms). The nulling times are the same for all values of S OF .

Composite dSIR filters (cdSIRs) with TI s = 350 ms and TI i = 500 ms. Attenuated first IR T 1 -filter (TI s ) in ( A ) and attenuated second IR T 1 -filter (TI i ) in ( B ). ( A , B ) show the conventional unattenuated T 1 -bipolar filter (blue) with S OF = 1, an attenuated first TI s filter (S OF = 0.5) (red) and a further attenuated first TI s filter (S OF  = 0.25) (yellow).

In Figure 5 A, attenuation of the first IR filter with TI s is shown with S OF set at 1 (blue), 0.5 (orange), and 0.25 (yellow). The yellow and orange curves are wider than the unattenuated dSIR curve (blue) and are seen around the outside of the first (negative) pole of the blue curve at the first TI s . At the second positive pole, the yellow and orange curves are narrower than the unattenuated blue curve and are seen inside it. This results in a broadening, loss of contrast, and lower signal white matter around the first (negative) pole, as well as increased contrast and narrower boundaries between white and gray matter around the second (positive) pole.

In (A), as S OF is decreased from 1.0 to 0.5 and 0.25, the two latter filters become wider around the first (negative) pole and are positioned outside the blue filter. At the second (positive) pole, the attenuated filters are inside the blue filter. They show higher slopes.

(B) shows the conventional T 1 -bipolar filter (blue) with S OF = 1, an attenuated TI s filter with S OF = 0.5 (red), and a further attenuated TI s filter with S OF = 0.25 (yellow). As S OF is attenuated, the S OF = 0.5 and S OF = 0.25 filters around the first (negative) pole are situated inside the blue curve, become narrower, and have higher slopes. The attenuated filters around the second (positive) pole are situated outside the blue curve. They are wider and show lower slopes. For T 2 , a short T 2 increases attenuation relative to a longer T 2 , and this corresponds to the narrower and sharper peak, with greater negative contrast and spatial resolution of the contrast in (A).

In Figure 5 B, attenuation of the second IR filter with TI i is shown. As S OF is decreased to 0.5 and 0.25, the filter narrows around the inside of the blue filter at the first (negative) pole and widens around the outside of the blue filter at the second (positive) pole. The negative contrast produced for the same difference in T 1 is increased around the first pole and decreased around the second pole.

The same principles can be applied to the lSIR filter. Composite (c) forms of the bipolar filters can be designated as cSIR, cdSIR, clSIR, etc.

Susceptibility and magnetization transfer (MT) can also be used to attenuate signals and produce supplementary contrast. The combination of T 1 and T 2 * contrast may be of particular value in demonstrating the paramagnetic rim sign and the central vein sign in MS.

3. Methods

With approval from the New Zealand Health and Disability Ethics Committee (EXP 11360, 2022), and informed consent from each subject, MR scans were performed on four adult normal controls and nine adult patients with MS during relapse and remission or with suspected MS (one case). A 3T scanner (General Electric Healthcare Premier) was used. Two-dimensional IR fast spin echo (FSE) sequences were performed with a TIs nulling normal white matter, and a longer TIi was chosen to produce narrow mD dSIR images targeted at small increases in the T 1 of white matter ( Figure 2 C). Two-dimensional and three-dimensional wide mD dSIR images with a short TI s and a long TI l were also obtained. Synthetic narrow mD dSIR images were created from wide mD dSIR images [ 1 ], and dSIR images were used to synthetically produce lSIR images. Positionally matched 2D and 3D T 2 -wSE and/or T 2 -FLAIR images were acquired, as well as filtered susceptibility weighted images ( Table 1 ).

Table 1 Pulse sequences and pulse sequence parameters. # Sequence TR (ms) TI (ms) TE (ms) Matrix Size Voxel Sizes (mm) Number of Slices Slice Thickness (mm) 1 2D FSE IR (for white matter nulling) 9192 350 7 256 × 224 26 4 0.9 × 0.1 Z512 0.4 × 0.4 2 2D FSE IR (used with #1 for narrow mD dSIR) 5796 500 7 256 × 224 26 4 0.9 × 0.1 Z512 0.4 × 0.4 3 2D FSE IR (used with T 1 for wide mD dSIR) 5796 800 7 256 × 224 26 4 0.9 × 0.1 Z512 0.4 × 0.4 4 3D BRAVO (for white matter nulling) 2000 400
256 × 256 220 0.8 0.8 × 0.8 Z512 5 3D BRAVO (used with #4 for wide mD dSIR) 2000 800
256 × 256 220 0.8 0.8 × 0.8 Z512 6 2D T 2 -FLAIR 6300 1851 102 320 × 240 26 4 0.7 × 0.7 Z512 0.4 × 0.4 7 3D T 2 -FLAIR without/with fat saturation 6300 1850 102 256 × 256 252 0.8 0.8 × 0.8 Z512 0.6 × 0.6 8 3D susceptibility weighted 40 - 32 300 × 300 110 2 0.8 × 0.8 Z512 Z = zipped.

Pulse sequences and pulse sequence parameters.

Z = zipped.

4. Illustrative Cases

Figure 6 shows mid-ventricular images of a 41-year-old female patient with MS in remission. No abnormality is seen on the T 2 -wSE image ( Figure 6 A). On the narrow mD dSIR image ( Figure 6 B), normal peripheral white matter is dark and has a low signal (thick arrows). The more central superior longitudinal fasciculi show a higher signal with a gradient of signal decreasing from posterior to anterior. Within them are the corticospinal tracts (short thin arrows). Three focal lesions are seen in the peripheral white matter and at the leucocortical junctions (long thin arrows).

Forty-one-year-old female with MS in remission. Comparison of 2D T 2 -wSE ( A ) and narrow mD dSIR ( B ) images. No abnormality is seen on the T 2 -wSE image, but three focal lesions are seen on the dSIR image (long thin arrows). The corticospinal tracts are also seen (short thin arrows). The normal superior longitudinal fasciculi are of intermediate (posterior) to low (anterior) signal in ( B ). More peripheral white matter is normal and has a low signal in ( B ) (thick arrows). A high signal boundary is seen between white matter and cortical grey matter as well as between white matter and CSF around the lateral ventricles in ( B ).

At a supraventricular level in the same patient ( Figure 7 ), the T 2 -wSE image is again normal ( Figure 7 A). The corresponding narrow mD dSIR image shows only a small region of low signal normal white matter (dark arrow). The corticospinal tracts are seen (short thin white arrows), as well as a lesion (long thin white arrow). There are widespread asymmetric and patchy abnormalities in the white matter.

Forty-one-year-old female patient with MS in remission (as for Figure 6 ). Two-dimensional T 2 -wSE ( A ) and narrow mD dSIR ( B ) images at the same level. No abnormality is seen in ( A ). A focal lesion is seen in ( B ) (long thin white arrow) and the corticospinal tracts show a high signal (short thin white arrows). In addition, there is widespread, patchy increased signal in white matter (short thick white arrows) with only a small region showing a normal or near normal low signal (long black arrow). High contrast and high spatial resolution contrast are seen at the boundaries between normal white matter and normal gray matter in ( B ). These features are less obvious in areas where the white matter shows abnormal high signal.

Figure 8 shows positionally matched supraventricular T 2 -FLAIR ( Figure 8 A) and narrow mD dSIR ( Figure 8 B) images in a patient with MS during a relapse. A single lesion is seen on the T 2 -FLAIR image, and this is also seen on the dSIR image (long white arrows). An additional six lesions are only seen on the dSIR image (short white arrows). Many of the lesions on the dSIR image have high signal boundaries (rims). In addition, there are bilateral symmetrical widespread relatively uniform increases in signal in white matter, with some sparing of more peripheral white matter. These are features of a high grade (4–5) (maximum grade 5) whiteout sign [ 6 ]. This differs from the normal dark appearance of white matter seen on the narrow mD dSIR image in Figure 6 B. No evidence of a whiteout sign is seen on the T 2 -FLAIR image.

Thirty-two-year-old female patient with MS undergoing a relapse. T 2 -FLAIR ( A ) and synthetic narrow mD dSIR ( B ) images. On the T 2 -FLAIR image, one lesion is seen (long arrow). The surrounding white matter appears normal. On the dSIR image ( B ), the lesion shown on the T 2 -FLAIR image is seen (long arrow) as well as six other lesions (short arrows). Most of the white matter in ( B ) is high signal corresponding to a high grade 5 (out of 5) whiteout sign [ 7 ]. This is in contradistinction to the appearance of the peripheral white matter in the patient with MS in remission shown in Figure 6 B. where the peripheral white matter is low signal.

Figure 9 and Figure 10 show a 38-year-old patient with MS in remission ( Figure 9 A and Figure 10 A, left columns) and during a relapse two years and five months later ( Figure 9 B and Figure 10 B, right columns) imaged with the same narrow mD dSIR sequence. Figure 9 shows three positionally matched lower levels in the brain and Figure 10 shows two positionally matched higher levels in the brain. White matter shows a generally low signal during remission (whiteout sign grade 1–2) ( Figure 9 A and Figure 10 A), and a high signal (whiteout sign grade 4–5) during the relapse ( Figure 9 B and Figure 10 B). The multiple levels within the brain show the wide distribution of the high grade whiteout sign in the cerebellar and cerebral hemispheres, as well as in the brainstem. No evidence of a whiteout sign was seen on the corresponding T 2 -FLAIR images.

Thirty-eight-year-old female patient with MS in remission ( A , left column) and during a relapse ( B , right column) two years and five months later. Matching narrow mD dSIR images at three lower levels in the brain. In remission (left column), there are bilateral symmetrical areas of low signal in the white matter of the cerebellar and cerebral hemispheres. The corresponding areas show increased signal during the relapse (right column) consistent with a grade 4–5 (out of 5) whiteout sign. No evidence of a whiteout sign was seen on the T 2 -FLAIR images.

Thirty-eight-year-old female patient with MS in remission ( A , left column) and during a relapse ( B , right column) two years and five months later (same case as in Figure 9 ). Matching narrow mD dSIR images at two higher levels in the brain. In remission, white matter shows a low signal (left column). This is increased during the relapse in a bilateral symmetrical distribution consistent with a grade 4–5 (out of 5) whiteout sign (right column). No evidence of a whiteout sign was seen on the T 2 -FLAIR images.

Figure 11 shows narrow mD dSIR images in a normal adult control ( Figure 11 A) and in a 77-year-old patient with MS ( Figure 11 B) during a relapse. In addition to the whiteout sign, there is a loss of contrast between gray and white matter in the thalamus of the patient ( Figure 11 B). Also, the heads of the caudate nuclei, as well as the insular and peripheral cortices, appear isointense with CSF on the dSIR image. These are grayout signs. No evidence of a whiteout sign or grayout signs was seen on the corresponding T 2 -FLAIR images.

Skull-stripped images of a normal control ( A ) and 77-year-old patient with MS during a relapse ( B ). There is low signal in the normal white matter in ( A ) and a whiteout sign in ( B ). In addition, the gray matter in the thalamus and cortex has a uniform low signal and is nearly isointense with CSF. These are grayout signs. No evidence of a whiteout sign or grayout signs was seen on the positionally matched T 2 -FLAIR images.

Figure 12 shows a 41-year-old female patient with MS during a relapse. Wide mD dSIR ( Figure 12 A) and phase filtered susceptibility weighted gradient echo ( Figure 12 B) images are shown. The dSIR image shows well defined high signal boundaries around two lesions ( Figure 12 A, white arrows). These lesions show less obvious paramagnetic rim signs on the filtered susceptibility weighted images ( Figure 12 B, white arrows). The high signal in Figure 11 A could be due to increased T 1 in the lesions beyond the second T 1 nulling value and/or reduction in T 1 in long T 1 lesions due to free iron.

Forty-one-year-old female patient with MS during a relapse. Wide mD dSIR ( A ) and phase filtered susceptibility weighted gradient echo ( B ) images. The dSIR images show well defined high signal boundaries around two lesions in ( A ) (white arrows). These lesions show less obvious rim signs on the susceptibility weighted images ( B ) (white arrows).

Figure 13 shows a leucocortical lesion in a 41-year-old female patient with MS in remission. The lesion appears blurred and relatively featureless on the narrow mD dSIR image ( Figure 13 A), but shows a disrupted boundary within the lesion on the lSIR image ( Figure 13 B). Figure 13 C shows dSIR (blue) and lSIR (orange) signal profiles across the lesion. These are plots of signal vs. distance in mms on the image. The lSIR profile has higher signal and generally steeper slopes than the dSIR profile, corresponding to the graphs in Figure 4 .

Forty-one-year-old female patient with MS. A leucocortical lesion is shown in the right medial frontal lobe on the narrow mD dSIR image ( A ) and the matching synthetic lSIR image ( B ) (arrows). There are also left to right profiles with signal plotted against position (in mm) for the dSIR (blue) and lSIR (orange) images ( C ) at the level of the horizontal arrows shown in ( A , B ). No boundary between white matter and gray matter is seen within the lesion in ( A ). A disrupted high signal boundary between white matter and gray matter is seen in the lesion in ( B ). The lSIR profile (orange) has higher signal and generally steeper slopes than the dSIR profile (blue) in ( C ). The difference in signal (or contrast) achieved for the same change in position is generally greater with the lSIR filter.

Figure 14 shows another leucocortical lesion in a 24-year-old female patient with MS in remission. dSIR ( Figure 14 A) and cdSIR ( Figure 14 B) images are compared. The cdSIR image shows higher contrast. In addition, the frontal white matter has a more uniform low signal intensity on the cdSIR image. These are features consistent with the graphs in Figure 5 A.

Twenty-four-year-old female patient with MS in remission (TI s = 350 ms, TI i = 500 ms). Narrow mD dSIR ( A ) and composite (T 1 and T 2 ) cdSIR (TI s /TE s = 350/7 and 80 ms; TI i /TE i = 500/7 ms) ( B ) images. A leucocortical lesion is seen on the dSIR image ( A ) and with higher contrast on the cdSIR image ( B ) (arrows). White matter and gray matter boundaries show higher contrast and are narrower on the composite filter cdSIR image ( B ). Also, white matter is more uniformly low signal in ( B ). These features are consistent with the attenuation of the first IR TI s filter signal increasing contrast and narrowing boundaries at the positive pole and decreasing these at the negative pole as shown in Figure 5 A.

Figure 15 shows T 2 -FLAIR ( Figure 15 A) and wide mD dSIR ( Figure 15 B) sagittal images of the upper cervical spinal cord in a 43-year-old female patient with MS in remission. The T 2 -FLAIR image shows a poorly defined smudge of increased signal (white arrow). In the corresponding position, the dSIR image ( Figure 15 B) shows a high-contrast lesion with sharply defined boundaries, which is much more extensive than in ( Figure 15 A) (lower three arrows). An additional lesion is seen in the medulla on the dSIR image (highest arrow), but is not seen on the T 2 -FLAIR image.

Forty-three-year-old female patient with MS in remission. Sagittal 3D T 2 -FLAIR ( A ) and 3D wide mD dSIR ( B ) images. The T 2 -FLAIR image shows a poorly defined area of increased signal in the cervical cord (arrow). The dSIR image shows a high contrast lesion with sharply defined boundaries, which is much more extensive than in ( A ) (lower three arrows). An additional lesion is seen in the medulla on the dSIR image (highest arrow) ( B ), but not on the T 2 -FLAIR image.

Figure 16 shows the upper cervical spinal cord in a 42-year-old female patient with MS in remission. T 2 -FLAIR ( Figure 16 A), T 2 -wSE ( Figure 16 B), and wide mD dSIR ( Figure 16 C) images are compared. A large lesion is seen on all three images, but with greatest contrast on the dSIR image (long white arrows). In addition, three small lesions are only seen on the dSIR image ( Figure 16 C, short white arrows).

Forty-two-year-old female patient with MS in remission. Sagittal T 2 -FLAIR ( A ), T 2 -wSE ( B ), and wide mD dSIR ( C ) images. A large lesion is seen on all three images but with higher contrast on the dSIR image (long arrows). Three small lesions are only seen on the dSIR image (short arrows).

In a patient with optic neuritis and suspected MS, Figure 17 A,B (upper row) show axial fat saturated T 2 -FLAIR ( Figure 17 A) and narrow mD dSIR ( Figure 17 B) images of their optic nerves. Figure 17 C,D (lower row) show parasagittal oblique fat saturated T 2 -FLAIR ( Figure 17 C) and narrow mD dSIR ( Figure 17 D) images of the left optic nerve. The right optic nerve appears normal in Figure 17 A,B. The left optic nerve shows a distal abnormality on the T 2 -FLAIR axial and parasagittal images (white arrows), but shows proximal and distal abnormalities on the corresponding dSIR images (white arrows).

Patient with optic neuritis and suspected MS. The upper row shows axial fat saturated T 2 -FLAIR ( A ) and narrow mD dSIR ( B ) images. The lower row shows matched oblique fat saturated T 2 -FLAIR ( C ) and narrow mD dSIR ( D ) images through the left optic nerve. Distal changes are seen in the left optic nerve on the T 2 -FLAIR images (arrows) but both proximal and distal changes are seen in the left optic nerve on the dSIR images (arrows).

5. Discussion

Use of bipolar filter sequences such as dSIR, lSIR, and cdSIR demonstrated abnormal appearances in the brain, spinal cord, and optic nerve in MS patients which were not shown, or were only poorly shown, with T 2 -wSE and T 2 -FLAIR sequences. These included focal lesions, the whiteout sign, grayout signs, high signal boundaries/rims around lesions, disruption of boundaries between white and gray matter, and generalized changes in the optic nerve.

Unipolar filter IR sequences such as intermediate TI IR, STIR, MP-RAGE, and MP2RAGE have been employed in clinical MRI for many years, but bipolar filter sequences ( Table 2 ) are a new development [ 1 , 4 ]. Detail of the mathematics describing them is included in Table 3 . The equations also provide a basis for implementing synthetic bipolar sequences which can be produced from existing T 1 sequences or a combination of TP maps and synthetic bipolar filters.

Table 2 Bipolar filters. Bipolar Filter Reverse Bipolar Filter Tissue Property SIR rSIR T 1 dSIR drSIR T1 cdSIR cdrSIR T1, T2, T2*, D* lSIR lrSIR T1 clSIR clrSIR T1, T2, T2*, D* Synthetic SIR, dSIR, lSIR rSIR, drSIR, lrSIR T1 Synthetic cdSIR, clSIR cdrSIR, clrSIR T1, T2, T2*, D*

Bipolar filters.

Table 3 Bipolar filters signal equations and other functions. # Filter, Other Functions Signal Equation Figure # 1 IR, TI s S TIs = 1 − 2e −TIs/T 1 Figure 1 , Figure 2 and Figure 3 2 IR, TI i S TIi = 1 − 2e −TIi/T 1 Figure 1 , Figure 2 and Figure 3 3 SIR S SIR = S TIs − S TIi
Figure 1
4 dSIR

S dSIR = S TIs −   S TIi S TIs + + S TIi ( difference sum )

Figure 2 and Figure 3 5 cdSIR S dSIR = S TIs · S OF −   S TIi S TIs · S OF + S TIi  
S dSIR = S TIs −   S TIi · S OF S TIs + S TIi · S OF

Figure 5
6 cdSIR, S OF S OF = ±e −ΔTE/T2 , ±e −ΔTE/T2* , ±e −ΔbD* , etc.
Figure 5
7 dSIR, S dSIR S dSIR   ≈   ln   4 ∆ T I     T 1 − Σ T I ∆ T I (in mD)
Figure 2
8 dSIR, T 1 T 1 ≈ ∆ T I l n 4   S dSIR + Σ T I l n 4 (in mD)
Figure 2
9 lSIR S lSIR = ½(ln S TIs − ln S TIi )
Figure 4
10 clSIR

S 1 SIR = lnS Tis · S OF − lnS TIi


S 1 SIR = lnS Tis − lnS TIi · S OF


Figure 4
11 clSIR, lSIR S c 1 SIR = S c 1 SIR ± Δ TE T 2 ,   ± Δ TE T 2 * , ±ΔbD*, etc
Figure 4
12 lSIR, dSIR † S lSIR = atanh S dSIR
Figure 4
† The lSIR filter is the inverse hyperbolic tangent of the dSIR filter.

Bipolar filters signal equations and other functions.

† The lSIR filter is the inverse hyperbolic tangent of the dSIR filter.

UHC MRI with bipolar filter sequences uses IR sequences which already exist on most clinical MR systems and require minimal image processing. They can be implemented in a short time at very low cost and can be used at any clinical static field.

5.1. T 1 Measurements and Magnetization Transfer (MT)

The dSIR sequence is a T 1 map with a linear relationship between S dSIR and T 1 in the mD (Equation (4)). T 1 measurements obtained with dSIR sequences have been validated in phantom and human studies [ 7 , 8 ]. The observed values of T 1 (T 1obs ) are generally shortened by incidental MT effects arising from off-resonance 180° pulses when FSE data collections are used. MT results in a decrease in observed mobile proton density and a proportionate decrease in T 1obs . As a general rule, in diseased tissue compared with normal tissue, MT effects are decreased relative to normal. This results in a relative increase in T 1 in diseased tissue, which is synergistic with increases in T 1 arising in disease from other causes.

5.2. Signs

5.2.1. Whiteout Sign

The whiteout sign consists of a bilateral, symmetrical, widespread, generally uniform increase in signal in the white matter of the cerebral and cerebellar hemispheres, as well as the brainstem. The anterior and posterior central corpus callosum, as well as peripheral white matter of the cerebral hemispheres are usually relatively spared. Whiteout signs can be graded from one (normal) to five (abnormal) [ 6 ]. They are reversible and have been seen in mild traumatic brain injury (mTBI), hypoxic injury to the brain, cerebral tumors, long COVID, and MS. Whiteout signs are generally associated with neuroinflammation, although edema, demyelination, and degenerative change may also be implicated. When seen with the dSIR sequence nulled for normal white matter, they are due to widespread small increases in the T 1 of white matter which are insufficient to generate visible contrast with conventional clinical sequences.

5.2.2. Grayout Signs

Grayout signs can be manifest as a reduction or loss of contrast within a gray matter structure such as the thalamus, as well as reduction or loss of contrast between gray matter and white matter or between gray matter and CSF. On narrow mD dSIR sequences, a grayout sign can be caused by an increase in T 1 in gray matter within the hD. Not infrequently, grayout signs are seen with higher grade whiteout signs, and, thus are features of an encephalopathy rather than a leucoencephalopathy (when only white matter is involved).

High signal boundaries and lesions with narrow mD dSIR sequences can arise with an increase in T 1 in the lesion sufficient to cross the peak filter value and enter the hD. This corresponds with the dark rim around MS lesions seen with gray matter nulled double IR sequences, which occurs when there are relatively large increases in T 1 . This finding was seen more frequently in MS than in other diseases [ 9 ].

The high signal boundary/rim can also arise from a decrease in T 1 in an MS lesion induced by free iron from myelin at the edge of an MS lesion. The decrease in T 1 is from the hD back to the mD and passes through the peak of the bipolar filter.

High signal boundaries around lesions may be less obvious in the presence of a whiteout sign because of the widespread high signal in white matter, although many are apparent in Figure 8 B.

5.3. Clinical Issues

5.3.1. Activity

The usual signs of activity in MS are an increase in number and/or size with T 2 -weighted imaging in repeat studies, as well as gadolinium based contrast agent (GBCA) enhancement. To this, it may be possible to add the presence of a whiteout sign or increase in size or extent of a whiteout sign.

By using drSIR sequences sensitized to decreases in T 1 , it may be possible to increase the sensitivity of conventional IR sequences to GBCA enhancement by an order of magnitude, and, thus, increase the sensitivity of MRI to disease activity [ 1 ].

5.3.2. Acute Clinical Episodes with Stable MRI (ACES)

Clinical episodes without changes in MRI appearances were recorded in 26.1% of episodes in a real-world study of MS [ 10 ]. Clinical radiological mismatch in MS during relapse has also been described in other papers [ 11 , 12 ]. There is a need for greater MRI sensitivity to correlate better with clinical features. This could be provided by bipolar filter sequences.

Smoldering lesions are recognized by progressive increase in size of abnormalities on T 2 -weighted images and paramagnetic rim lesions without GBCA enhancement [ 13 , 14 , 15 , 16 , 17 ], and could benefit from more sensitive sequences. The same applies to the use of T 2 -FLAIR imaging and GBCA enhancement to assess therapeutic response. Paramagnetic lesion rims [ 18 , 19 , 20 , 21 ] and the central vein sign [ 22 , 23 , 24 , 25 , 26 ] could also benefit from increased sensitivity.

5.3.3. Diagnostic Criteria for MS

The core sequences for recognition of MS lesions are T 2 -wSE and/or T 2 -FLAIR sequences [ 27 , 28 , 29 , 30 ], and thus are based on changes in T 2 , not the changes in T 1 seen with dSIR sequences. The sensitivity of dSIR sequences to the presence of MS lesions is supported by the belief that increases in T 2 are accompanied by increases in T 1 , and so detection of either may be of similar clinical significance. The initial study of MS with MRI was performed with a T 1 -weighted IR sequence.

Conventional diagnostic criteria for MS treat patchy changes due to increased white matter signal seen with T 2 -weighted sequences as of no diagnostic significance. These features may be much more obvious with dSIR sequences ( Figure 7 ). In addition, whiteout signs may be seen in a characteristic pattern throughout the white matter of the brain.

5.3.4. Clinical Use

In clinical practice, it is possible to positionally match T 2 -FLAIR sequences with dSIR T 1 -bipolar filter (BLAIR) sequences. Larger changes in T 2 are shown by T 2 -FLAIR sequences and smaller changes in T 1 by T 1 -BLAIR sequences, which are, thus, complementary, as seen in Figure 8 . cdSIR, T 1 , T 2 -BLAIR sequences can be used to add T 2 -weighting to the T 1 -weighting of dSIR sequences.

5.4. Other Sequences Using Two IR Sequences

Two other sequences employing two IR sequences are the nearest comparison to the BLAIR sequences described in this paper.

The first is the MP2RAGE sequence which uses two IR sequences with different TIs [ 31 ]. These signals are multiplied together and divided by the sum of their squares. This results in a negative unipolar filter with slope for white matter greater than that of the original IR sequences [ 32 , 33 ].

The second is the FLAWS (fluid and white matter suppression) group of sequences, which also uses two IR sequences with different TIs [ 32 , 33 ] that are subtracted and divided by their sum. Compared with narrow mD dSIR sequences, the ΔTIs of FLAWS high contrast (FLAWShc) and FLAWS high contrast opposite (FLAWShco) are wide and the sequences are monotonic, not bipolar, because they use signed or phase-sensitive signal values, not magnitude values.

The FLAWSmin sequence takes the minimum value of the two IR sequences and produces a positive unipolar filter with a wide ΔTI. It has shown halo signs of increased signal at the margins of MS lesions in gray matter or at the leucocortical boundary [ 34 , 35 ]. It has similarities to the dSIR sequence.

5.5. Further Developments

Further developments include 2D and 3D registration of images with different TIs as part of the basic sequence, but also registration of images before and after GBCA administration and for serial studies at different examinations.

The T 1 , T 2 *-BLAIR sequence is being developed to produce synergistic contrast from paramagnetic effects due to free iron.

Longer TI values are being used to null blood, and so visualize synergistic T 1 and T 2 * effects due to central veins within MS lesions.

Particular variants of sequences designated to specifically see white matter changes in the spinal cord are being assessed together with narrow mD sequences with longer TIs for the thalamus.

It is possible to visualize lesions in the cortex using a longer second TI of 900 ms or 950 ms so that the high signal boundary is between the cortex and CSF not between white and gray matter. Boundaries can also be narrowed by the use of lSIR sequences rather than dSIR sequences.

6. Conclusions

Bipolar filter sequences promise a variety of options which appear well suited to imaging changes in the brain in MS. A program of technical development is in place to expand the range of available sequences and improve their effectiveness in diagnosis. Detailed clinical evaluation will be required. UHC MRI with bipolar filters could provide a substantial advance in the imaging of MS in clinical and research studies with MRI.

Abbreviations

BLAIR BipoLAr fIlteR, bipolar filter cdSIR Composite divided Subtracted Inversion Recovery clSIR Composite logarithmic then Subtracted Inversion Recovery dSIR Divided Subtracted Inversion Recovery hD Highest Domain IR Inversion Recovery lSIR Logarithmic then Subtracted Inversion Recovery mD Middle Domain MP-RAGE Magnetization Prepared-Rapid Acquisition Gradient Echo MP2RAGE Magnetization Prepared 2 Rapid Acquisition Gradient Echo MT Magnetization Transfer SIR Subtracted Inversion Recovery S OF Signal from Other Filter TP Tissue Property TP-bipolar filter Tissue Property-bipolar filter TP-filter Tissue Property-filter UHC Ultra-High Contrast

Author Contributions

Conceptualization, P.C., D.M.C., M.B., E.E.K., E.P., H.D.-M., C.S., G.N., M.S. and G.M.B.; methodology, P.C. and T.C.E.; software, D.M.C. and M.B.; validation, P.C. and M.B.; formal analysis, P.C.; investigation, P.C., D.M.C. and T.C.E.; resources, K.W., G.N. and S.J.H.; data curation, P.C., G.N., T.C.E. and M.S.; writing—original draft preparation, P.C. and G.M.B.; writing—review and editing, all; visualization, P.C., D.M.C., M.S. and G.M.B.; supervision, P.C., E.E.K. and S.J.H.; project administration, P.C. and S.J.H.; funding acquisition, P.C., G.N. and S.J.H. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was approval by the New Zealand Health and Disability Ethics Committee (EXP 11360, 2022).

Informed Consent Statement

Written informed consent has been obtained from each subject.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims.2020.04.07 ). G.M.B. is a consultant to Magnetica, Brisbane, Australia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Statement

We would like to acknowledge support from the Fred Lewis Enterprise Foundation; the Hugh Green Foundation; Manaaki Moves; NZ P Pull; the JN & HB Williams Foundation; the Mangatawa Beale Williams Memorial Trust; Multiple Sclerosis Society of New Zealand; Neurological Foundation (New Zealand); Trust Tairāwhiti; Friends of Mātai Blue Sky Fund; GE Healthcare; Mātai Ngā Māngai Maori and Kānoa—Regional Economic Development & Investment Unit of New Zealand.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

References

Associated Data

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.