Patent Description:
Cortical lesions are common in neurologic disease, including multiple sclerosis (MS). Pathological changes in the cerebral cortex in MS include demyelination, neuronal loss, gliosis, and loss of intracellular iron. There is evidence that the pathophysiology of these lesions differs from that of lesions in white matter. Cortical lesions, and especially subpial cortical lesions that touch the pial surface of the brain, may form independently from white matter lesions, perhaps due to leptomeningeal inflammation. In addition, cortical lesions may contribute independently to disability. MRI is an essential tool for clinical management of and research on MS and other neurological conditions, including diagnosis, prognosis, response to treatment, and outcome measures in clinical trials, as well as for providing insights into the underlying pathophysiology.

While cortical lesions are known from histopathology studies to be common in MS, they have so far been difficult to visualize on MRI, especially at clinically accessible magnetic field strength. Cortical lesions are difficult to detect in routine imaging due to the small dynamic range in signal changes induced by the lesions in comparison to the overall dynamic range. In addition, the close proximity of the cortical lesion, especially of the superficial or "subpial" type of lesion, to cerebrospinal fluid (CSF), can greatly obscure its visualization if the signal intensities from the two tissue types are similar. MRI at standard clinical magnetic field strength is almost completely insensitive.

At higher field (<NUM> tesla, 7T), cortical lesions have been detected using T2*-weighted images and T1 mapping sequences. The visibility is much reduced at lower fields (which are commonly available for clinical use, such as 3T), because of the changes to relaxation properties as well as lower signal to noise ratio (SNR) at lower field strengths. Currently available approaches that have been designed to detect cortical lesions at 3T - including double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) imaging - are more sensitive to these signal changes than more standard MRI techniques, but are still poorly sensitive to many cortical lesions, especially subpial lesions, which are thought to underlie substantial clinical disability.

DIR, a sequence with suppressed cerebrospinal fluid (CSF) and white matter signal, is limited by low signal and artifacts, leading to low sensitivity for cortical lesions and high false positive rates. When compared to postmortem pathology, 3T DIR was <NUM>% sensitive for leukocortical lesions, but only <NUM>% sensitive for subpial lesions. PSIR has also been used for cortical lesion visualization at 3T. While PSIR appears to improve sensitivity to leukocortical lesions, data on improvement in subpial lesion detection has been inconsistent. More recently, T1-weighted magnetization-prepared <NUM> rapid acquisition gradient echoes (MP2RAGE) and its derived images such as bias-free T1-weighted images and T1-maps, have been used for cortical lesion detection at 3T, with a similar cortical lesion detection rate as DIR, and at 7T.

T2*-weighted methods at 7T have also been used to image cortical lesions, with substantial improvement in subpial lesion detection rate in MS compared to 3T. The increased sensitivity of T2* weighting for cortical demyelination at ultra-high field is likely due to a combination of increased sensitivity to loss of myelin as well as to loss of iron. In addition, ultra-high field strength makes it easier to obtain higher resolution scans due to the increased signal-to-noise ratio (<NUM>-fold increase in signal-to-noise ratio at 7T compared to 3T), enabling detection of smaller lesions. Nevertheless, 3T clinical scanners could potentially be made more sensitive to subpial lesions by increasing the lesion contrast relative to surrounding tissue such as CSF and cortical gray matter through CSF-nulling and optimal parameter selection.

Accordingly, there is a need for better visualization of cortical lesions in order to understand their dynamics, their clinical importance, and their response to MS treatment. More accurate methods for visualizing cortical lesions are key to better understanding their clinical implications and their response to MS therapies. Improved visualization may also be relevant to disease differential diagnosis, prognostication, and detection of response to therapy.

The publication<NPL>) is a review article on methods of visualizing a cortical lesion in a subject using an MRI system available at the time.

Provided herein is an MRI system for use in carrying out a method of visualizing a cortical lesion in a subject using an MRI system. The MRI system may perform a MRI sequence described herein at a field strength of <NUM>, <NUM>, or <NUM> tesla (T), which in some examples may be <NUM> or <NUM> T. The method comprises acquiring signal data with the MRI system by performing a T2*-weighted sequence that suppresses cerebrospinal fluid (CSF) signals. From the signal data, one or more high resolution images are produced at a computer system of the MRI system. The high resolution images may be indicative of (demonstrate) the presence of cortical lesions.

The T2*-weighted sequence comprises a 3D-T2*-weighted multi-shot acquisition sequence, and furthers comprise a T2-prepared inversion pulse (T2Prep) followed by an inversion pulse. The T2Prep suppresses CSF signals, and the inversion time of the inversion pulse is tuned to the null point of CSF. The T2Prep may comprise a <NUM>x-<NUM>y(<NUM>)-<NUM>x pulse, and the duration of the T2-Prep pulse may be based on the calculated time at which gray matter (GM) and white matter (WM) signals are equal based on their initial magnetization values. The signal data acquired from the T2*-weighted sequence may be motion corrected before producing the one or more high resolution images. The one or more high resolution images may be processed from magnitude and phase images produced by the T2*-weighted sequence. The T2*-weighted sequence may comprise performing vascular crushing before the acquisition, which may suppress vascular signals. An echo train may be acquired in a centric fashion.

The method may further comprise performing one or more of a T1-weighted magnetization-prepared <NUM> rapid acquisition gradient echoes (MP2RAGE) sequence and a fluid-attenuated inversion recovery (FLAIR) sequence. The signal data produced by one or more of MP2RAGE and FLAIR may be used to produce one or more images. The one or more images produced by the T2*-weighted and one or more of MP2RAGE and FLAIR sequences may be indicative of the presence of the cortical lesion. The images produced by the T2*-weighted sequence may be compared to the images produced by the MP2RAGE or FLAIR sequences, or the combination thereof. The comparison may be used to demonstrate the presence or absence of the cortical lesion.

The T2*-weighted sequence may be repeated <NUM>-<NUM> times, and the signal data acquired from the sequences averaged to produce the one or more high resolution images. In one example, the T2*-weighted sequence may be performed twice. The average may be a voxel-wise median.

The invention provides an MRI system as defined in claim <NUM>, comprising an MRI device and a computer system. The MRI device comprises a magnet system to apply a polarizing magnetic field about at least a portion of a subject arranged in the MRI system; a plurality of gradient coils to apply a gradient field to the polarizing magnetic field; and, a radiofrequency (RF) system to apply a RF excitation field to a region of interest in the subject and acquire signal data therefrom. The polarizing magnetic field may be <NUM>, <NUM>, or <NUM> tesla. The computer system has a processor and a memory. The computer system is configured to perform a T2*-weighted sequence by controlling the MRI device, wherein the sequence is a 3D-T2*-weighted imaging sequence comprising inversion recovery susceptibility weighted imaging combined with enhanced T2 weighting, referred to as an IR-SWIET sequence, which suppresses CSF signals; acquire high resolution signal data generated by the sequence; and, produce one or more high resolution images from the signal data.

The T2*-weighted system comprises a 3D-T2*-weighted multi-shot acquisition sequence, and further comprises a T2-prepared inversion pulse (T2Prep) followed by an inversion pulse, wherein the T2Prep suppresses CSF signals. The T2Prep may comprise a <NUM>x-<NUM>y(<NUM>)-<NUM>x pulse, and the duration of the T2-Prep pulse may be based on the calculated time at which GM and WM signals are equal based on their initial magnetization values. The computer system is configured to tune the inversion time of the inversion pulse produced by the MRI device to the null point of CSF. The computer system may control the MRI device to repeat the T2*-weighted sequence <NUM>-<NUM> times, particularly twice; and, average the signal data acquired from the T2*-weighted sequences to produce the one or more high resolution images. The average may be a voxel-wise median. The computer system may motion correct the signal data acquired from the T2*-weighted sequence before producing the one or more high resolution images. The computer system may process magnitude and phase images produced by the T2*-weighted sequence to generate the one or more high resolution images.

The computer system may control the MRI device to perform vascular crushing before the acquisition to suppress vascular signals. The computer system may acquire an echo train in a centric fashion. The computer system may also control the MRI device to further perform one or more of a MP2RAGE and a FLAIR sequence, acquire MP2RAGE signal data and FLAIR signal data from these one or more sequences to produce one or more MP2RAGE high-resolution images, FLAIR high-resolution images, or a combination thereof. The one or more high-resolution images from the one or more T2*-weighted sequences may be compared to the high-resolution images from the one or more MP2RAGE and FLAIR sequences. The comparison may be indicative of a cortical lesion. In one example, the T2*-weighted sequence is performed twice in combination with the MP2RAGE and FLAIR sequences.

The inventors have discovered that T2*-weighted imaging at high-resolution, together with suppression of the CSF signal, is superior to other known methods for detecting cortical lesions, especially subpial lesions. The technique takes advantage of the T2* signal increase that is in part induced by reduced iron concentration in cortical lesions, and is deployed at high-resolution to allow visualization of small lesions and thin lesions that lay on the subpial surface of the brain.

Two distinct approaches have been tested by the inventors and are detailed herein. CSF suppression was achieved in high-resolution T2*-weighted sequences in the first approach, outside the scope of the present invention, through application of a diffusion gradient (DWI approach), and in the second, according to the invention, by selecting an inversion time (TI) corresponding to the null point of CSF (IR-SWIET approach).

Diffusion-weighted brain MR imaging, outside the scope of the invention, is used in standard clinical brain imaging at various clinical and non-clinical field strengths (including <NUM> and <NUM> T), mainly for detection of acute strokes and areas of active tissue destruction, as well as certain tumors. The inventors realized that commonly used diffusion imaging techniques employ the echo-planar imaging (EPI) sequence, which is uniquely sensitive to T2* and susceptibility changes in tissue. The inventors further recognized that images acquired at moderate-to-high b-value suppress the CSF signal, enabling sensitive imaging of T2* and susceptibility changes in tissue. In addition, diffusion tensor images are acutely sensitive to microstructural changes in tissue. This makes high-resolution diffusion images ideally suited for imaging iron loss and microstructural changes that occur in these lesions. Indeed, in imaging patients with MS, the inventors noticed that areas of subtle signal abnormality are frequently seen on diffusion-weighted images in the cortex of MS patients, which are substantially better seen on these images than on other scans obtained as part of the clinical routine. Similar lesions have not been observed in healthy volunteers or in patients with other neuro-inflammatory and neuro-infectious diseases, who are frequently imaged under similar clinical protocols.

Specifically, the first approach - the DWI approach, outside the scope of the present invention - may use large diffusion gradients to suppress CSF, EPI acquisition at a relatively short echo time (TE) of <NUM>-<NUM> for better SNR, and a scheme to acquire images at high resolution of about <NUM> per voxel edge. The inventors optimized the pulse sequence parameters to achieve high resolution while also optimizing lesion visualization. To achieve reliable visualization (good SNR), despite higher resolution and longer sampling time required to achieve it, a relatively lower TE of ~<NUM> may be used. Monopolar diffusion gradients and a moderate b-value of <NUM>-<NUM>/mm<NUM> may be used to achieve this. The modifications may be accomplished utilizing the options already available on a Siemens 3T scanner, or other scanners commonly used in the art. The images may be acquired with <NUM> orthogonal or <NUM> or more non-colinear directions of the diffusion gradient, and the non-zero b-value images may be averaged for visualizing the DWI trace. Further improvements in SNR can be achieved by signal averaging the acquisition in each diffusion direction <NUM>-<NUM> times. The resulting diffusion-weighted trace image also has T2* weighting from the EPI acquisition, which is essential for visualization of cortical lesions. Trace-DWI can be produced on the scanner and used directly. It may also be useful to remove any motion that occurred during acquisition, and motion correction using registration can be done prior to averaging off-line for better results.

The second approach, according to the invention, is to suppress CSF in an optimal high-resolution 3D-T2*-weighted image using inversion recovery susceptibility weighted imaging (SWI) with enhanced T2-weighting (IR-SWIET). While SWI images can be generated from the magnitude and phase images acquired using the IR-SWIET technique, the inventors have discovered that the magnitude images are sufficient for visualization of cortical lesions. Some cortical lesions are visible on routine high-resolution multishot 3D-T2*-weighted images, but a majority of them are difficult to identify due to the high signal from CSF. The T2-prepared inversion recovery multishot acquisition along with appropriate contrast enhancement mechanism employed in an IR-SWIET sequence reduces many of the false-positive hyperintensities seen in high-resolution diffusion-weighted images. In addition, modification to suppress artifactual hyperintense vessel signal has been implemented. The images produced on an MRI scanner can be used directly for visualization. The sequence can be repeated <NUM>-<NUM> times and averaged for increased SNR. Motion correction may be used before averaging and visualization to improve the image quality.

The inventors have determined that, for both the DWI and IR-SWIET approaches, phased-array coils greatly improve visualization of the abnormal MRI signal in cortical lesions due to improved signal-to-noise ratio in superficial brain structures. In particular, the two approaches provide dramatic improvements over standard T2-FLAIR, T2, and T1-weighted sequences, as well as modifications thereof that are in general clinical use for visualizing cortical lesions.

Provided herein is a system for carrying out an MRI method for detecting cortical lesions, which may be subpial. The method may be performed on a subject, which may be an animal, and which may further be a mammal such as a primate or ape, or more specifically a human. The subject may have or may be suspected to have MS, epilepsy, or suffered from a stroke, or he/she may have another disease process that affects the cerebral cortex, such as dysplasia or neurodegeneration. In one example, the subject may have or be suspected to have MS.

In particular, provided herein is a system for carrying out a method of producing an image indicative of the cortical lesion using an MRI system. The method may comprise acquiring data with the MRI system by performing a high resolution T2*-weighted sequence that suppresses CSF signals. The T2* weighting may be used to detect T2* signal increases induced by reduced iron concentrations, as well as microstructural changes, in cortical lesions.

A method outside the scope of the invention may comprise diffusion-weighted imaging (DWI), which may be performed at a magnetic field strength of <NUM> or <NUM> tesla (T). The DWI may comprise at least one EPI sequence. The DWI sequence may comprise large diffusion gradients to sensitize diffusing spins. The EPI acquisition may be performed at an echo time (TE) of <NUM>-<NUM>, which may be used to acquire images at a near-isotropic resolution of about <NUM> per voxel edge.

The DWI sequence may also comprise monopolar diffusion gradients, and comprise moderate b-values, in order to suppress CSF signals (typically ranging between <NUM>-<NUM>/mm<NUM>). Images may be acquired with <NUM> orthogonal or <NUM> or more non-colinear directions of the diffusion gradient. Non-zero b-value images may be averaged to visualize the DWI trace. The method may comprise acquiring repetitions of the sequence (typically <NUM>-<NUM> repetitions). The individual acquisitions may be averaged to increase the SNR. Trace-DWI may be produced on the MRI scanner and may be used directly to visualize cortical lesions. Motion that occurred during acquisition may be mitigated using registration prior to averaging, which may be performed off-line.

The DWI sequence may comprise simultaneous multislice imaging or highly parallel imaging In an example outside the scope of the present invention, the DWI sequence may comprise the sequence shown in <FIG>. In such a sequence, the depicted gradients may be monopolar diffusion gradients as described above. In another example outside the scope of the present invention, the DWI sequence may comprise the following parameters:.

The MRI system used to implement the method may comprise phased-array coils.

According to the invention, the T2*-weighted sequence comprises optimal high-resolution 3D-T2*-weighted imaging, which comprises inversion recovery susceptibility weighting combined with enhanced T2 weighting (referred to as IR-SWIET). The method comprises an inversion recovery (IR) multishot acquisition with an inversion time (TI) tuned to the null point of CSF, and T2-preparation to enhance T2 contrast in the images.

The IR-SWIET sequence may maintain T2* contrast similar to a 3D SWI sequence known in the art, and introduce T2 contrast at null point of CSF using T2-preparation. SWI images may be generated from the magnitude and phase images acquired using the IR-SWIET pulse sequence, but the magnitude images may be sufficient for visualization of cortical lesions. The parameters for the IR-SWIET may also correspond to 3D SWI, as known in the art. In particular, the parameters may comprise the following:.

The IR-SWIET sequence is as shown in <FIG>. The IR-SWIET-generated images may be acquired at steady-state, which may be as indicated in <FIG> (arrow). In one embodiment, the echo train may be acquired centrically. A SWI sequence known in the art or as described herein may be modified to suppress CSF using <NUM>x-<NUM>y(<NUM>)-<NUM>x T2Prep followed by inversion and acquisition at CSF-null point, which may be similar to known preparation for 3D FLAIR, as described in <NPL>.

The IR-SWIET sequence may exhibit T2 weighting from a shorter T2-preparation pulse, which produces hyperintense signal from cortical lesions. The duration of the T2-Prep pulse may be based on the calculated time at which GM and WM signals are equal based on their initial magnetization values. In one embodiment, the T2 preparation before inversion may comprise delay = <NUM>; inversion recovery duration = <NUM>; and, improved lesion contrast using T2-Prep = <NUM>. The IR-SWIET sequence may use 3D segmented EPI acquisition with bipolar vascular crushing gradients set to crush blood velocities greater than <NUM>/s. The IR-SWIET sequence may also comprise the following acquisition parameters: FOV = <NUM><NUM>; res: <NUM>*<NUM>*<NUM><NUM>; sagittal acquisition; y-SENSE = <NUM>; z-SENSE = <NUM>; z-SENSE = <NUM>; Proset (for water excitation) <NUM> pulse. Several different combinations of acquisition parameters and inversion times listed above may achieve similar results. In one embodiment, the IR-SWIET sequence may be repeated <NUM>-<NUM> times and the results averaged, which may increase the SNR. The average may be a voxel-wise mean or median. In one example, the average may be a voxel-wise median. The IR-SWIET method may also comprise motion correction before averaging and visualization. The images produced by the MRI scanner may be used directly for visualization of cortical lesions.

In another example, images generated using an IR-SWIET sequence described herein may be viewed alongside one or more MRI sequences to more sensitively and accurately identify cortical lesions. These may include one or more standard clinical MRI sequences such as MP2RAGE, FLAIR, or high-resolution conventional T2*-weighted gradient-echo images. In one example, the IR-SWIET sequence may be combined with a MP2RAGE sequence, a FLAIR sequence, or the combination thereof. In one example, both MP2RAGE and FLAIR sequences are performed. The IR-SWIET sequence may be repeated <NUM>-<NUM> times, and the signal data from the IR-SWIET sequences may be averaged. In one example, the IR-SWIET sequence is repeated twice and the signal data from the repeated sequences are averaged. The average may be a voxel-wise median. A comparison of images generated by the IR-SWIET sequence, and the MP2RAGE or FLAIR sequences or the combination thereof may be used to identify cortical lesions. In particular, the images may be compared side-by-side.

Provided herein is an MRI system according to claim <NUM> for detecting cortical lesions. The MRI system is configured to perform one or more of the MRI methods described herein. The MRI system comprises a MRI device, which may comprise a magnet system to generate a polarizing magnetic field about at least a portion of a subject arranged in the MRI system, a plurality of gradient coils to apply a gradient field to the polarizing magnetic field, and a radiofrequency (RF) system to apply an RF excitation field to a region of interest in the subject and acquire MR image data therefrom. The MRI system may also comprise a computer system, having a processor and memory, the computer system programmed to perform a pulse sequence described herein that suppresses CSF signals by controlling the MRI device, and acquires signal data generated using the pulse sequence. The computer system may also reconstruct a set of images from the acquired signal data and identify a cortical lesion by analyzing the set of images for a visual signature. The computer system may further determine a neurological disease state using the identification of one or more cortical lesions.

In one embodiment, the MRI system comprises a Philips 3T ACHIEVA™ Scanner, which may comprise a <NUM>-channel head coil. The Philips scanner may be particularly useful for the IR-SWIET method described herein. In another embodiment, the MRI system comprises a Siemens 3T scanner. The Siemens scanner may be particularly useful for the DWI method described herein, which is outside the scope of the present invention.

The MRI system may comprise one or more phased-array coils.

The systems of the invention can be used in a method to assist in diagnosing and evaluating a neurological condition. The presence of one or more cortical lesions may be indicative of a neurological condition, or may be used in assessing the prognosis or response to treatment of the neurological condition. The neurological condition may be multiple sclerosis (MS), traumatic brain injury, stroke, epilepsy, or any other condition that affects the cerebral cortex. Images produced by the MRI methods described herein may also provide clinically useful information about lesions in other portions of the central nervous system.

The present invention has multiple aspects, illustrated by the following non-limiting examples.

This example demonstrates that two different approaches based on high-resolution T2*-weighted sequences that suppress CSF signals (the DWI approach, which is outside the scope of the present invention, and the IR-SWIET approach, according to the invention) are capable of detecting cortical lesions better than existing approaches.

<FIG> show the schematics for the IR-SWIET and DWI approaches.

<FIG> shows that a T2*-weighted sequence that includes inversion pulse with acquisition at null point of CSF and with T2-preparations (IR-SWIET) and the DWI approach improve the visualization of cortical lesions as compared to a T2*-weighted or FLAIR sequence alone.

This example demonstrates the design and evaluation of a 3D sequence (IR-SWIET) that suppresses CSF while maintaining T2* contrast with additional T2 weighting for visualizing cortical and white matter lesions in MS. Multiple sclerosis is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. Iron deposition visualized through T2*-weighted imaging has been thought to be a surrogate biomarker for different lesion characteristics (<NPL>). Iron concentration changes have been observed in newly forming lesions of MS patients (<NPL>), while central veins visualized by SWI or similar approaches may be a distinguishing feature of MS lesions (<NPL>).

3D interleaved echo planar imaging (EPI) (<NPL>) or spiral imaging (<NPL>) provide rapid SWI of the entire brain with high resolution in a relatively short time. SWI provides important information regarding iron deposition and lesions in multiple sclerosis, but cortical lesions cannot be readily visualized in this method, probably due to the low in-plane resolution or persistent T1-weighting in the acquisition. Similar limitations exist for clinical FLAIR and T1-weighted images which fail to reliably show cortical lesions due to low resolution and lack of adequate T2*-weighting or presence of residual T1-weighting.

We compared cortical lesion visualization independently on IR-SWIET (median signal from <NUM> acquisitions), magnetization-prepared <NUM> rapid acquisition gradient echoes (MP2RAGE), double inversion recovery (DIR), susceptibility weighted imaging (SWI), and phase sensitive inversion recovery (PSIR) images for <NUM> adults with MS. We also identified cortical lesions with a multimodal reading of IR-SWIET (median of <NUM> acquisitions), MP2RAGE, and fluid attenuated inversion recovery (FLAIR) images for each case. Lesions identified on 3T images were verified on "gold standard" 7T T2* and MP2RAGE images.

The aim was to suppress CSF while maintaining T2 and T2* contrast similar to a 3D SWI sequence. Bloch simulation for SWI (<FIG> and <FIG>) shows the signal evolution for gray matter (GM), white matter (WM), and CSF. T1/T2 and proton density values from literature were used (<NPL>; <NPL>; <NPL>; <NPL>) along with parameters corresponding to 3D SWI (Table <NUM>). Acquisition was performed at steady-state (<FIG>, arrow).

The SWI sequence was modified to suppress CSF using <NUM>x-<NUM>y(<NUM>) -<NUM>x T2Prep followed by inversion similar to preparation for 3D FLAIR (<NPL>). Since magnetization for GM recovers at a slower rate than for WM, GM-lesion-WM T2 contrast is compromised at CSF null. To compensate for the lower GM longitudinal magnetization, a shorter duration T2-Prep pulse was introduced prior to EPI acquisition to provide T2-weighting. This T2-Prep duration was based on calculated time at which GM and WM signal are equal based on their initial magnetization values. The final sequence is shown schematically in <FIG>, along with magnetization evolution. Improved T2-weighting was obtained by acquiring the echo train in a centric fashion.

Ten adults with MS and two healthy adults (see Table <NUM> for cohort details) underwent scans on a 3T scanner (Philips Achieva <NUM> T; Philips Healthcare, Eindhoven, the Netherlands) equipped with a <NUM>-channel head coil, including optimized IR-SWIET, acquired four times in each scanning session, FLAIR, DIR, PSIR, and SWI (see Table <NUM> for sequence parameters).

For the MS cases, previously acquired 3T MP2RAGE images (3T Magnetom Skyra, Siemens, Erlangen, Germany, equipped with a <NUM>-channel head coil) and 7T MP2RAGE and T2*-weighted gradient recalled echo (GRE) images (7T whole-body research system, Siemens, equipped with a single-cannel transmit, <NUM>-channel phased array receive head coil) were also used for comparison. 7T scans were acquired <NUM>-<NUM> months (median <NUM> months) before the 3T scans.

MP2RAGE 3T and 7T processing to generate uniform images was performed on the respective scanners as a part of the Siemens research sequence package (Work-in-Progress Package #900D). IR-SWIET repetitions were coregistered (ANTS, Advanced Normalization Tools, github. com/ANTsX/ANTs), and the voxel-wise median of the first <NUM> or all <NUM> acquisitions was generated. The median was used, rather than the mean, to decrease the contribution of outlier values that may arise due to noise or motion. All images were aligned to the 7T MP2RAGE uniform denoised images using linear coregistration (AFNI, Analysis of Functional NeuroImages, afni.

Cortical lesions were manually segmented using the software package Display (github. com/BIC-MNI/Display) developed at the McConnell Brain Imaging Center of the Montreal Neurological Institute.

Cortical lesions were identified and marked on all 3T images by an experienced neurologist (with ><NUM> years' experience in cortical lesion segmentation). Cortical lesions were identified on 3T IR-SWIET single acquisition (IR-SWIETx1), IR-SWIET median of two acquisitions (IR-SWIETx2), IRSWIET median of four acquisitions (IR-SWIETx4, see <FIG> and Table <NUM> for comparison of IRSWIET averages), DIR, PSIR, FLAIR, SWI, and MP2RAGE images independently in random order, with at least <NUM> week in between analysis of each sequence from the same subject.

In addition, two 3T multicontrast reads were performed for each subject: (<NUM>) IR-SWIETx2, MP2RAGE, FLAIR; (<NUM>) DIR, MP2RAGE, FLAIR. Cortical lesions were segmented on 7T images using both MP2RAGE and T2*w GRE images. This segmentation was done by <NUM> raters independently (one neurologist with ><NUM> years' experience and one neuroradiologist with ><NUM> years' experience), followed by a consensus read by both raters. On 3T and 7T images, cortical lesions were classified as leukocortical, intracortical, or subpial. Lesion volume was calculated for each cortical lesion identified on 7T images using the MP2RAGE images.

Following identification of cortical lesions on all 3T images, each marked lesion was compared to the 7T images used as a "gold standard" for cortical lesion segmentation. Each lesion was classified as a true cortical lesion, a juxtacortical lesion, a false positive if no correlate was seen on 7T images, or a false negative cortical lesion if a lesion was seen on 7T images only in retrospect. Lesions identified on 3T images that were out of the field of view (FOV) on the 7T images (which do not cover the inferior regions of the temporal and occipital lobes) were classified as out-of- FOV and were not included in the quantitative analyses of lesion detection. For lesion detection analyses, cortical lesion subtype was determined based on the appearance of each lesion at 7T, as subtyping was difficult at 3T.

Purely intracortical (i.e., non-subpial) lesions seen on 7T images were virtually undetected on all of the 3T images, with only <NUM> intracortical lesions identified on 3T images for all <NUM> cases. Thus, intracortical lesions are included in the total cortical lesion analysis but were not separately analyzed.

Contrast to noise ratio (defined as (SI1-SI2)/(SI1+SI2)) was measured in <NUM> lesions (intracortical, leukocortical, and periventricular), which were depicted on all sequences after registration and reformatting.

The Friedman test was used to compare detected lesion number, sensitivity, and volume between individual sequences. Spearman correlation coefficients were calculated when comparing number of subpial lesions identified on 3T vs 7T. A linear mixed effects model was used to determine the effect of 3T sequence on subpial classification accuracy, with subject included in the model as a random intercept. Post-hoc pairwise comparisons between individual sequences and IR-SWIETx4 as well as comparisons between the two multimodal reads were performed. As this was an exploratory study, p-values, when <<NUM>, were reported directly without adjustment for multiple comparisons.

On IR-SWIET images, there was low contrast between gray and white matter, and the CSF signal was effectively suppressed. MS lesions in the white matter, deep gray matter, brainstem, and cortex are clearly visualized (<FIG>). In many cases, central veins, which are a hallmark of MS lesions, could be seen within lesions (<FIG>). However, there was very little differentiation between gray and white matter, making distinction between juxta- and leuko-cortical lesions difficult based solely on the IR-SWIET images.

Table <NUM> shows CNR measurements (weighted by size) obtained from the three lesion subtypes for all sequences on a subset of <NUM> cases. Table <NUM> provides total lesion volumes analyzed on the same subset of <NUM> cases.

IR-SWIET and DIR showed similar contrast for all three types of lesions studied, while SWI showed the poorest contrast. Intracortical lesions on DIR, although hyperintense compared with WM/CSF, were sometimes almost isointense with surrounding unaffected GM. MP2RAGE had comparable contrast as IR-SWIET and DIR for leukocortical lesions but poorer contrast for intracortical lesions due to hypointensity and proximity to suppressed CSF.

More subpial lesions were detected on IR-SWIET.

Images from <NUM> adults with MS were used to identify cortical lesions independently on IRSWIETx2 and x4, other state-of-the-art sequences used to detect cortical lesions (DIR, PSIR), and standard clinical MRI sequences (MP2RAGE, FLAIR, SWI). A similar number of total cortical lesions were identified on each of the individual 3T sequences (Table <NUM>, <FIG>).

While IR-SWIET did not improve detection of leukocortical lesions, there was a significant improvement in subpial lesion detection. A total of <NUM> true positive subpial lesions (per case median <NUM>, average sensitivity vs. 7T <NUM>%) were detected on IR-SWIETx4, compared to <NUM> (median <NUM>, sensitivity <NUM>%, sensitivity vs IR-SWIETx4 p=<NUM>) on MP2RAGE and <NUM> (median <NUM>, sensitivity <NUM>%, p<<NUM>) on DIR. The percentage of lesions classified as false positive did not differ between sequences. No cortical lesions were detected on any combination of IR-SWIET images in either of the two healthy volunteers who were scanned. In addition, more cases had at least one subpial lesion on IR-SWIETx4 (<NUM> of <NUM> cases) than any of the other 3T sequences: MP2RAGE (<NUM>/<NUM>), FLAIR (<NUM>/<NUM>), DIR (<NUM>/<NUM>), SWI (<NUM>/<NUM>), and PSIR (<NUM>/<NUM>).

To simulate a real-world scenario in which multiple image types are used to identify cortical lesions, we identified cortical lesions on two multicontrast reads: IR-SWIETx2, MP2RAGE, and FLAIR and DIR, MP2RAGE, and FLAIR. IR-SWIETx2 was used instead of IR-SWIETx4 as the improvement in subpial lesion sensitivity between the two was small and the shorter scan time of IR-SWIETx2 (~<NUM> vs ~<NUM>) is more clinically feasible. We compared the lesions identified on the <NUM> multimodal reads with lesions identified on 3T MP2RAGE alone to determine if inclusion of IR-SWIET or DIR, neither of which is used routinely on clinical MRI scans, improves subpial sensitivity over the more standard 3T MP2RAGE sequence. The multimodal read of IR-SWIETx2, MP2RAGE, and FLAIR improved average cortical lesion sensitivity vs MP2RAGE alone (<NUM>% vs <NUM>%, p<<NUM>). The IR-SWIETx2/MP2RAGE/FLAIR multimodal read was also more sensitive for subpial lesions (<NUM>%) compared to DIR/MP2RAGE/FLAIR (<NUM>%, p<<NUM>) or MP2RAGE alone (<NUM>%, p<<NUM>) (Table <NUM>, <FIG>,<FIG>). At least one subpial lesion was detected in more cases on the multimodal read that included IR-SWIET (<NUM>/<NUM>) than on the read that included DIR (<NUM>/<NUM>).

Although IR-SWIET increases the number of detected subpial lesions substantially, the number of subpial lesions identified on 3T remained lower than the number detected on 7T. A maximum of <NUM>% of subpial lesions identified on 7T images were detected on 3T images using a combination of IR-SWIETx2, MP2RAGE, and FLAIR. We investigated the impact of cortical lesion size measured on 7T MP2RAGE on the detectability of lesions at 3T. For each sequence, the average size of detected lesions was greater than the average size of undetected lesions (p<<NUM> for each sequence, <FIG>). When sensitivity of each of the 3T sequences for subpial lesions was calculated in terms of cortical lesion volume rather than number, we found a similar relationship between the 3T sequences, with generally higher sensitivity when calculated by volume, likely due to higher sensitivity for larger subpial lesions (<FIG>). There was no difference between the average size of detected lesions among individual 3T sequences (<FIG>). The proportion of detected subpial lesions on IR-SWIET images increased with lesion volume (<FIG>).

Cortical lesion subtype categorization was done for all of the above analyses based on 7T images. Cortical lesion subtype was also determined on 3T images. We determined the percentage of subpial lesions identified on images from each 3T sequence that were correctly classified as subpial on the 3T read. On IR-SWIETx4, <NUM> ± <NUM>% of identified subpial lesions were categorized correctly, vs <NUM> ± <NUM>% on IR-SWIETx2, <NUM> ± <NUM>% on MP2RAGE (p<<NUM> vs IR-SWIETx4), <NUM> ± <NUM>% on FLAIR (p<<NUM>), <NUM> ± <NUM>% on DIR (p<<NUM>), <NUM> ± <NUM>% on SWI (p=<NUM>), and <NUM> ± <NUM>% on PSIR (p=<NUM>) (<FIG>). On the IR-SWIETx2/MP2RAGE/FLAIR multimodal read, an average of <NUM> ± <NUM>% of the detected subpial lesions were correctly classified, versus only <NUM> ± <NUM>% on the DIR/MP2RAGE/FLAIR multimodal read (p<<NUM>) (<FIG>). Less than <NUM>% of true cortical lesions were misclassified as subpial on any of the individual sequence or multimodal reads.

We next examined the relationship between the number of subpial lesions identified on 7T and the number of lesions identified as subpial on each of the 3T sequences and the two multimodal reads. False positive and incorrectly classified lesions identified on 3T were included in this analysis. For the single 3T sequences, correlation was highest for IR-SWIETx2 (r=<NUM>, p<<NUM>). Correlations for other sequences were as follows: IR-SWIETx4 (r=<NUM>, p<<NUM>), SWI (r=<NUM>, p<<NUM>), FLAIR (r=<NUM>, p<<NUM>), PSIR (r=<NUM>, p=<NUM>), MP2RAGE (r=<NUM>, p=<NUM>), and DIR (r=<NUM>, p=<NUM>) (Figure 13B). The correlation for each of the multimodal reads were similarly high (r=<NUM>, p<<NUM> for IR-SWIETx2/MP2RAGE/FLAIR and r=<NUM>, p<<NUM> for DIR/MP2RAGE/FLAIR) (<FIG>).

In this study, we report the development and optimization of a new MRI sequence, IR-SWIET, with high-resolution, CSF-suppressed T2* weighted images for better visualization of MS cortical lesions, especially subpial lesions, at 3T. White matter, deep gray matter, brainstem, and cerebellar lesions are also visible on IR-SWIET images at 3T. In addition, central veins are clearly seen in white matter and infratentorial lesions. While the sequence was developed and tested in MS, we expect that it will have broad applicability for detection and characterization of a wide range of central nervous system disorders in which the cortex may be affected: potentially including infarction, neoplasm, epilepsy, and congenital/developmental anomalies.

Being EPI based, IR-SWIET could exhibit sensitivity to spatial and temporal variations in B0 field homogeneity caused by susceptibility effects and time-varying eddy currents. Reducing scan time or using dynamic correction techniques can help ameliorate such effects. Employing multiple T2-Prep pulses only modestly increased SAR to <NUM>% of the allowed maximum for a person of average weight.

Accurate optimization for IR-SWIET parameters based on Bloch simulation is confounded by the range of T1/T2 values for WM and GM reported in literature (<NPL>). Different combinations of parameters (including shorter shot duration) are possible albeit with slightly different CNR. In addition, combining magnitude and phase images could provide additional information on lesion characterization, similar to SWI.

CNR as defined here does not change substantially with increased scan time. This was verified for SWI with NSA = <NUM> instead of <NUM>.

In MS, when cortical lesion identification was compared between IR-SWIET and other 3T methods, we found that more leukocortical lesions were identified with MP2RAGE than with IR-SWIET. Most of the leukocortical lesions seen on MP2RAGE were visible in retrospect on IR-SWIET. These lesions were likely missed on the initial IR-SWIET review due to the lack of cortex-white matter contrast on these images, leading to misclassification of leukocortical lesions as juxtacortical or subcortical lesions, which were not counted.

In contrast, subpial lesion sensitivity was higher for IR-SWIET than for FLAIR, DIR, SWI, and PSIR. Although there was no statistical difference for the comparison with MP2RAGE, our qualitative impression, which might be borne out quantitatively in a larger study, is that subpial lesions are less conspicuous on MP2RAGE (example in <FIG>). In addition, more subpial lesions were identified on a multimodal read that included IR-SWIET, MP2RAGE, and FLAIR compared to the multimodal read that included DIR, MP2RAGE, and FLAIR, and more cases were found to have subpial lesions with IR-SWIET, both on individual sequence and multimodal reads. Finally, subpial lesion classification was much more accurate using IR-SWIETx2, MP2RAGE, and FLAIR than with DIR, MP2RAGE, and FLAIR.

Nevertheless, the sensitivity of any combination of the 3T scans for subpial lesions remained low compared to 7T MP2RAGE (at most <NUM>% with the IR-SWIETx2, MP2RAGE, and FLAIR multimodal read). This is to some extent expected given the improvement in signal-to-noise and contrast-to-noise ratios at ultra-high field, and differences in imaging resolution (<NUM> isotropic sequences at 7T vs <NUM>-<NUM> in plane resolution at 3T). In addition, the total acquisition time was much higher on 7T compared to 3T: a total of 1hr <NUM> for 7T vs <NUM> for 3T (IR-SWIETx2, MP2RAGE, and FLAIR). While some of the lesions seen on 7T were likely missed on 3T due to their small size, other lesions were likely missed due to low contrast between some cortical lesions and normal appearing gray matter. Finally, the 7T "gold standard" lesions were identified by two raters vs. only one rater for the 3T images. Even at 7T, there is significant interrater variability, usually due to lesions missed by a single rater but confirmed as true lesions on a consensus read.

Despite the missed subpial lesions on 3T images, the correlation between the number of subpial lesions identified on IR-SWIET images and the number identified on 7T images was high compared to other 3T sequences. This comparison included false positive 3T lesions and lesions misclassified as subpial on 3T, and thus simulates a scenario in which no 7T gold standard exists for comparison. Given the close correlation between 3T and 7T subpial lesion number using IR-SWIET and the improved accuracy of subpial classification using this method, associations between subpial lesion number measured on 3T IR-SWIET and clinical and MRI metrics are likely to be similar to what would be found if subpial lesions were measured on 7T images, but with the advantages that 3T MRI is much more accessible in a clinical setting, total scan time is much shorter, and whole-brain coverage is more easily attained.

The focus in this study was on cortical lesion visualization, but white matter and brainstem lesions are also very prominent on IR-SWIET images, as are central veins within lesions. Further dedicated analysis into the utility of this sequence more broadly for MS - where it could potentially substitute for FLAIR and/or susceptibility-weighted imaging - as well as for other conditions, is warranted. In addition, phase images, which were not analyzed here, or a combination of phase and magnitude images, may provide additional information on lesion characterization. Finally, since T1 relaxation plays a role in the IR-SWIET contrast mechanism, the utility of post-gadolinium IR-SWIET acquisition for detection of both parenchymal and leptomeningeal enhancement could also be explored.

In summary, IR-SWIET, when combined with a T1-weighted sequence such as MP2RAGE, allows effective cortical lesion visualization and is much more feasible than 7T methods. We favor an average of two IR-SWIET acquisitions for the best balance of subpial lesion sensitivity and scan time. Associations between subpial cortical lesions, disability, and progressive forms of MS can now be determined in much larger cohorts of patients than has been possible with 7T and with much higher sensitivity and accuracy than has been possible with current 3T methods. Cortical lesions detected with IR-SWIET could also be incorporated into clinical trials, which may be essential as we do not currently know if drugs that are effective at inhibiting white matter lesion formation also prevent subpial cortical lesion formation. In addition, cortical demyelination has been studied mainly in the context of MS and there is some evidence that it may be specific to MS, but IR-SWIET could be used to study larger cohorts with other inflammatory and noninflammatory brain diseases to determine how specific subpial demyelination is to MS. Ultimately, IR-SWIET could be incorporated into clinical scans to improve accuracy of MS diagnosis and prognosis, and help to measure response to treatment.

Claim 1:
A magnetic resonance imaging (MRI) system comprising:
(a) an MRI device comprising:
(i) a magnet system configured to apply a polarizing magnetic field about at least a portion of a subject arranged in the MRI system;
(ii) a plurality of gradient coils configured to apply a gradient field to the polarizing magnetic field; and,
(iii) a radiofrequency (RF) system configured to apply a RF excitation field to a region of interest in the subject and acquire signal data therefrom; and,
(b) a computer system, having a processor and memory, configured to:
(i) perform a T2*-weighted sequence by controlling the MRI device, wherein the T2*-weighted sequence is a 3D-T2*-weighted imaging sequence comprising inversion recovery susceptibility weighted imaging combined with enhanced T2 weighting, referred to as an IR-SWIET sequence, comprising a T2-prepared inversion pulse (T2Prep) followed by an inversion pulse, wherein the T2Prep suppresses CSF signals by tuning the inversion time of the inversion pulse to the null point of CSF;
(ii) acquire high resolution signal data generated by the sequence; and,
(iii) produce one or more high resolution images from the signal data.