Early MS Detection with Modified T2W FLAIR Sequence: Research Proposal

This research proposal, submitted by Merlin James Paul for an MSc in Diagnostic Imaging, investigates the potential of a modified T2W FLAIR sequence for enhanced precision and early detection of Multiple Sclerosis (MS). The study aims to determine if the inclusion of modified T2W FLAIR sequences can allow earlier detection of MS. The background section provides a comprehensive review of relevant literature, including T1 and T2 relaxation times, MRI sequences (T1-weighted, T2-weighted, and FLAIR), and the importance of accurate MS lesion detection, particularly in the cervical spine. The methodology outlines the process, including patient and control selection, consent acquisition, MRI acquisition using 3 Tesla MRI, and detailed MRI analysis, along with the calculation of T1w/T2w and sT1w/T2w ratios. This research is significant because it aims to improve the accuracy of MS diagnosis and potentially improve patient outcomes. The study proposes two sagittal FLAIR sequences with different TR times to assess the quality of cervical spinal cord MR images.

Research Proposal: MSc (Diagnostic Imaging subject)
N.B. Single spacing and font size 12 Times New Roman should be used. Do not exceed the space given in
any section.
Student's name:
Merlin James Paul
Proposed title: Should be concise and informative
Enhanced precision along with early Multiple Sclerosis detection with modified T2W FLAIR sequence.
Overall research question: A single question should summarise the aim of the project
Will the inclusion of modified T2W FLAIR sequence technique allow ealier detection of Multiple
Sclerosis?
Brief summary of proposed study:
Multiple sclerosis (MS) is an immune-mediated inflammatory illness that attacks myelinated axons in the
central nervous system, destroys myelin and axon at varying degrees and causes imperative physical
damage in over 30 percent of patients within 20–25 years. When many cells are demolished, the body
ultimately loses its capacity to perform ordinary tasks regulated by those nerve cells, resulting in confusion
and miscommunication between the brain and other body components. These lesions leads to complicated
symptoms along with motor shortcomings in addition to sensory shortcomings.
MS can be very difficult to diagnose, they also have numerous variation of signs and symptoms as there is
no specific symptom for MS.
The T2W FLAIR sequences have the capacity to suppress the cerebrospinal fluid (CSF) signal intensity
that usually exhibits elevated signal intensity in T2-weighted MR pictures reflecting this water-based
tissue's lengthy T2 relaxation time. By eliminating the fluid signal by using an original 180 inversion RF
pulse followed by a lengthy TI interval of 2500 ms before applying the 90-180 RF pulse mix, FLAIR
cervical spine diagnostic images provide the opportunity for enhanced MS plaque detection within the
cervical cord.
The literature-based evidence attributes this enhancement to the achievable heavy T2-weighting with this
sequence, along with a decrease in flow artifacts overlying the cervical spinal cord owing to the
suppression of CSF signal, resulting in enhanced visualization clarity of any high-signal MS plaques within
the cord.
Reviewing the routine imaging protocol, it was not investigated how to improve the accuracy of imagery of
MS plaques, especially in C-spine. This research proposal is therefore essential and it will be interesting to
see if adding two T2W FLAIR or perhaps just one axial 3DT2W FLAIR sequence would provide more
precise and enhanced diagnostic images while analysing the c-spine MS plaques.
Therefore, enhanced precision along with early Multiple Sclerosis detection with T2W FLAIR sequence
technique has been proposed.

What is the background to this proposed research? Present a concise, referenced review
of literature relevant to your topic. This should give some justification for what you plan to
investigate, it should set the context for your work, and demonstrate the relevance to Diagnostic
Imaging. Use the Harvard referencing system.
Tissue can be defined by two distinct periods of relaxation namely theT1 and T2. T1 (longitudinal
relaxation time) is the constant time that determines the rate of return to equilibrium of excited
protons. It is a measure of the moment taken to realign with the internal magnetic field for spinning
protons. T2 (transverse relaxation time) is the time constant that determines the rate at which excited
protons achieve equilibrium or leave each other out of contact (Krauss et al. 2018).
TR or Repeat Time is the amount of time between successive pulse sequences applied to the same
slice of the brain being imaged while TE or Time to Echo is the time between the RF pulse delivery
and the echo signal receiving. T1-weighted and T2-weighted scans are the most prevalent MRI
sequences. Using brief TE and TR times, T1-weighted images are generated (Gabr et al. 2019).
Tissue characteristics predominantly determine the contrast and brightness of the image. By contrast,
using longer TE and TR times, T2-weighted images are generated. The contrast and brightness in
these images are predominantly determined by the tissue transverse relaxation time or T2
(Maranzano et al. 2019).
The formation of MS lesions generates a hydrophilic atmosphere results in the rise of T2 and proton
density-weighted MR signal and a decrease in T1-weighted scans. A radiological characteristic of
MS is the avoidance of hyper-intense regions on T2-weighted MR imaging.
FLAIR is a T2-weighted scan that uses an inversion pulse to selectively suppress CSF. However, at
the cost of decreased SNR, the suppression of the CSF signal emerges. Usually, FLAIR scans are
obtained in 2D parallel to the subcallosal line. In order to reliably detect callous corpus lesions,
additional sagittal FLAIR scans are required. 2D-FLAIR also has CSF and blood flow artifacts and
often offers inadequate T2 weighting that requires extra proton density / T2-weighted pictures to
detect lesions in infratentorial fields (Cooper et al. 2019).
In order to diagnose MS lesions, FLAIR imaging is highly essential. Improving the detection of MS
lesions in the spinal cord on MR pictures is essential for two reasons (Maranzano et al. 2019). First,
when diagnosing MS, cord lesions may boost trust as cord lesions do not grow with ageing. They are
therefore more MS-specific than cerebral white matter lesions (Dickerson et al. 2017). In addition,
cord lesions can be seen with ordinary brain results in patients with a suggestive clinical image of
MS. Second, cord injury causes acute MS symptoms more frequently than brain injury (Cooper et al.
2019).
Only in more than 95 percent of patients, MRI demonstrates focal or confluent defects in white
matter (Nakamura et al. 2017). However, their existence alone is not diagnosing multiple sclerosis.
The most common mistake is to allow multiple sclerosis to be diagnosed in patients with progressive
disease at a single site (generally spinal) where a structural lesion is not excluded (Schmidt et al.
2019).
In multiple sclerosis (MS), the combination of three-dimensional T2-weighted (T2w) and fluid-
attenuated inversion retrieval (FLAIR) images can enhance brain lesion visualization (Gabr et al.
2019). An ideal way of altering and modifying the sequences and combination of T2W and FLAIR,
however, has not yet been defined. The primary goal of this research proposal is to explore an ideal
sequence of T2w and FLAIR to enhance the precision of visualizing the MS lesions.
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List the references quoted in the review:
Cooper, G., Finke, C., Chien, C., Brandt, A. U., Asseyer, S., Ruprecht, K., & Scheel, M. (2019).
Standardization of T1w/T2w ratio improves detection of tissue damage in multiple sclerosis. Frontiers
in neurology, 10, 334.
Dickerson, E., Davenport, M. S., Syed, F., Stuve, O., Cohen, J. A., Rinker, J. R., & Collaborative, M. R.
Q. (2017). Effect of template reporting of brain MRIs for multiple sclerosis on report thoroughness and
neurologist-rated quality: results of a prospective quality improvement project. Journal of the American
College of Radiology, 14(3), 371-379.
Fatehi, D., Naleini, F., Salehi, M. G., Gharib, A., Farzizadeh, M., & Rostamzadeh, A. (2016).
Evaluation of multiple sclerosis patients through structural biomarkers of diffusion tensor magnetic
imaging and correlation with clinical features. Journal of Chemical and Pharmaceutical Sciences, 9(2),
830-837.
Gabr, R. E., Hasan, K. M., Haque, M. E., Nelson, F. M., Wolinsky, J. S., & Narayana, P. A. (2016).
Optimal combination of FLAIR and T2‐weighted MRI for improved lesion contrast in multiple
sclerosis. Journal of Magnetic Resonance Imaging, 44(5), 1293-1300.
Krauss, W., Gunnarsson, M., Nilsson, M., & Thunberg, P. (2018). Conventional and synthetic MRI in
multiple sclerosis: a comparative study. European radiology, 28(4), 1692-1700.
Maranzano, J., Dadar, M., Arnold, D. L., Collins, D. L., & Narayanan, S. (2019). Automated
Separation of Diffusely Abnormal White Matter from Focal White Matter Lesions on MRI in Multiple
Sclerosis. bioRxiv, 727818.
Nakamura, K., Chen, J. T., Ontaneda, D., Fox, R. J., & Trapp, B. D. (2017). T1‐/T2‐weighted ratio
differs in demyelinated cortex in multiple sclerosis. Annals of neurology, 82(4), 635-639.
Schmidt, P., Pongratz, V., Küster, P., Meier, D., Wuerfel, J., Lukas, C., & Weber, F. (2019). Automated
segmentation of changes in FLAIR-hyperintense white matter lesions in multiple sclerosis on serial
magnetic resonance imaging. NeuroImage: Clinical, 23, 101849.
Wider justification and importance of the work: Explain why the reseacrh is appropriate as
an MSc study, and its broader relevance to health care.
In the previous 50 years, the result for MS patients has risen comparatively, particularly in the 1990s.
MRI imaging became progressively accessible and subsequently used for the diagnosis of MS patients.
Since the amount and place of MRI-detected MS plaques adds to the classification of diseases according
to the McDonald criteria, any sequence that has the ability to enhance this process is well-intentioned for
investigation.
On this ground, this study will form the first portion of an investigative method and assess the quality of
the cervical spinal cord MR pictures obtained using two FLAIR sequences with different TR times. By
using quantitative methods for calculating SNR (signal-to-noise ratio) and CNR (contrast-to-noise ratio)
together with particular image quality criteria related to SNR, CNR and SR and an appropriate scoring
scheme, images obtained with the two sequences will be assessed to determine which T2W-FLAIR
sequence provides the highest quality for a specified moment of scanning and should then be included in
the routine MS MR scanning protocol at the clinical center.
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State the proposed hypotheses:
Proposed Hypothesis:
H1: The inclusion of modified T2W FLAIR sequence technique allow earlier detection of Multiple
Sclerosis
Null Hypothesis:
H0: The inclusion of modified T2W FLAIR sequence technique allow earlier detection of Multiple
Sclerosis.
Detail the methodology that will be used to test the hypotheses: Give a concise, but
detailed account of all aspects of the proposed methodology in chronological order, to include details of
all data collection, and plans for data analysis.
Detailed methodology for testing the hypothesis is as followed
A. Patients and Controls
After the approval is obtained from the hospital, patient and control individuals must be included
after identifying the individuals using the hospital database (Zhao et al. 2016).
B. Acquiring consent
After identifying the target test and control population for the imaging trial protocol, comprehensive
consent must be acquired from all the individuals before performing the procedure (Palmour et al.
2017).
C. MRI Acquisition
MRI acquisition might be performed on 3 Tesla MRI (Tim Trio, Siemens Medical Systems,
Erlangen, Germany). By eliminating the fluid signal through the use of an initial 180 inversion RF
pulse followed by a long TI interval of 2500 ms before application of the 90-180 RF pulse
combination, FLAIR images of the cervical spine offer the potential for improved MS plaque
detection within the cervical cord.
 Sagittal FLAIR Sequence 1: Long TR, TR1: 8000 ms and another parameters TE: 114 ms; TI:
2500 ms; FOV read: 330mm; FOV phase: 75%; slice thickness: 3.0 mm; NEX: 2; no. slices: 11;
base resolution: 256; phase resolution: 100%; turbo factor (ETL): 27; echo train per slice: 8;
voxel size: 1.3×1.3× 3mm and acquisition time: 4:34 minutes.
 Sagittal FLAIR Sequence 2: Shorter TR, TR2: 6000 ms another TE: 114 ms; TI: 2500 ms; FOV
read: 330mm; FOV phase: 75%; slice thickness: 3.0 mm; NEX: 2; no. slices: 11; base resolution:
256; phase resolution: 100%; turbo factor (ETL): 27; echo train per slice: 8; voxel size: 1.3×1.3×
3mm and acquisition time: 4:34 minutes.
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D. MRI Analysis
The T1w, T2w and FLAIR images will be then processed before the calculation of the T1w / T2w
and sT1w / T2w ratio. By eliminating the fluid signal by using an original 180 inversion RF pulse
followed by a lengthy T1W interval of 2500 ms before applying the 90-180 RF pulse mix, FLAIR
cervical spine pictures provide the opportunity for enhanced MS plaque detection within the cervical
cord.
E. T1w/T2w Ratio and sT1w/T2w Ratio Calculation
By separating the drawn 3D T1w picture by the spatially recorded 3D T2w picture, the T1w / T2w
ratio was calculated using the FSL statistics tool. A scaling factor was discovered to calculate the
sT1w / T2w ratio by separating the average intensity value in the T1w picture by the median
intensity value of the NAGM in the T2w image (Righart et al. 2017). The T2w image will be then
enhanced by scaling factor to create a scaled T2w image (sT2). The sT1w/T2w ratio was then
calculated using the equation from (Misaki et al. 2015):
sT1w/T2w ratio= T1w−sT2/ T1w+sT2
F. Statistical Analysis
The statistical analysis will be performed to determine the significance of the modified T2W FLAIR
sequence to generate the enhanced MRI images. T-tests and t-2 tests were used to evaluate the
picture accuracy of group variations. First, NAWM's inter-subject variation in T1w / T2w andsT1w /
T2w was evaluated using the variation coefficient (CoV) and contrasted with the cv-equality set
using the Feltz & Miller test. Comparison of group variations between MS patients using t-tests
(T1w, T2w, T1w / T2w, sT1w / T2w) (Ghassemi et al. 2014). Using Pearson's correlation, the
connection between T1w / T2w and sT1w / T2w ratio intensity values has also been explored. To
assess appropriate covariates for each measure in NAWM, analyze the mean intensity values of T1w,
T2w, T1w / T2w, and sT1w / T2w using linear models using a step-by-step technique backwards. A
model was constructed for each intensity of the tissue, including group, age and sex as predictors
(Hagiwara et al. 2018). This frequency was then decreased and one non-significant predictor was
removed at a moment until only important predictors were included in the model. It would refer to
the Akaike Information Criteria where reduced values mean better fit and the best fit mixture would
be chosen (Yu 2016).
The volume and count of T2 lesions, EDSS and duration of the disease would be included as specific
factors for improving the technique's accuracy (Iwatani et al. 2015). It also included the interaction
between the duration and progression of the disease (Naganawa et al. 2018). For both the analyzes,
the stepwise linear regression was performed using the package Modern Applied Statistics with S.
By evaluating the Cook’s difference, each linear regression was also screened for the impacts of
extreme values. Cook's difference of >1 would indicate that an extreme value was overly influencing
the regression model (Soun et al. 2017). The significance threshold for all analyses was set at p <
0.004, using Bonferroni correction for multiple comparisons (Hernández et al. 2017).
Therefore, the statistical analysis would aid in establishing the enhancement of the precision in MS
lesion detection with the modified T2W FLAIR sequence, thereby verifying the hypothesis and
asserting whether H1 or H0 is right.
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List the references quoted in the methodology:
Ghassemi, R., Narayanan, S., Banwell, B., Sled, J. G., Shroff, M., Arnold, D. L., & Canadian Pediatric
Demyelinating Disease Network. (2014). Quantitative determination of regional lesion volume and
distribution in children and adults with relapsing-remitting multiple sclerosis. PloS one, 9(2), e85741.
Hagiwara, A., Hori, M., Kamagata, K., Warntjes, M., Matsuyoshi, D., Nakazawa, M., & Irie, R. (2018).
Myelin Measurement: Comparison Between Simultaneous Tissue Relaxometry, Magnetization Transfer
Saturation Index, and T 1 w/T 2 w Ratio Methods. Scientific reports, 8(1), 10554.
Hernández, M. D. C. V., Ferguson, K. J., Chappell, F. M., & Wardlaw, J. M. (2017). New multispectral
MRI data fusion technique for white matter lesion segmentation: method and comparison with
thresholding in FLAIR images. European radiology, 20(7), 1684-1691.
Iwatani, J., Ishida, T., Donishi, T., Ukai, S., Shinosaki, K., Terada, M., & Kaneoke, Y. (2015). Use of
T1‐weighted/T2‐weighted magnetic resonance ratio images to elucidate changes in the schizophrenic
brain. Brain and behavior, 5(10), e00399.
Misaki, M., Stanley, J. A., & Raz, N. (2015). Test–retest reliability and concurrent validity of in vivo
myelin content indices: Myelin water fraction and calibrated T1w/T2w image ratio. Human brain
mapping, 38(4), 1780-1790.
Naganawa, S., Satake, H., Iwano, S., Kawai, H., Kubota, S., Komada, T., & Fukatsu, H. (2018).
Contrast-enhanced MR imaging of the brain using T1-weighted FLAIR with BLADE compared with a
conventional spin-echo sequence. European radiology, 18(2), 337.
Nakamura, K., Chen, J. T., Ontaneda, D., Fox, R. J., & Trapp, B. D. (2017). T1‐/T2‐weighted ratio
differs in demyelinated cortex in multiple sclerosis. Annals of neurology, 82(4), 635-639.
Palmour, N., Affleck, W., Bell, E., Deslauriers, C., Pike, B., Doyon, J., & Racine, E. (2017). Informed
consent for MRI and fMRI research: analysis of a sample consent documents. BMC medical
ethics, 12(1), 1.
Righart, R., Biberacher, V., Jonkman, L. E., Klaver, R., Schmidt, P., Buck, D., & Geurts, J. J. (2017).
Cortical pathology in multiple sclerosis detected by the T 1/T 2‐weighted ratio from routine magnetic
resonance imaging. Annals of neurology, 82(4), 519-529.
Soun, J. E., Liu, M. Z., Cauley, K. A., & Grinband, J. (2017). Evaluation of neonatal brain myelination
using the T1‐and T2‐weighted MRI ratio. Journal of Magnetic Resonance Imaging, 46(3), 690-696.
Yu, D. (2016). Conditional Akaike Information Criteria for a class of poisson mixture models with
random effects. Journal of Statistics, 43(4), 1214-1235.
Zhao, L., Mugler, J., Wei, X., Chen, N., Mulkern, R., Panych, L., & Jolesz, F. A. (2016). A high-
resolution clinical whole-brain scan using single-slab three-dimensional T1W, T2W and FLAIR fast
spin-echo sequences. Proceedings of the International Society of Magnetic Resonance in Medicine.
Honolulu, Hawaii, 1294.
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State any agreed collaboration in the research, or any initial contacts that have been
made:
The MRI Department
 The radiographers will perform imaging on suitable patients and will randomize these as per the
study criteria.
 A panel of image evaluators will be drawn from expert personnel of this hospital for the
evaluation of the images.
 The clinical specialist will guide this process, identifying experts in the field.
 The radiographers involved in the study will also assess the technique for ease of use, confidence
in identifying the MRI protocol will form part of the image evaluation panel.
Permission / Approval: For projects that the Board of Studies has indicated permission or ethical
approval must be sought, detail the process and timescale that must be followed. For other projects,
insert not applicable.
A detailed proposal will be submitted to the Connoly Hospital Blanchardstown and will wait for the
response.
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Duration of work and timeplan: Give a chronological breakdown of the tasks that will be
completed during the research.
September, 2019 – Submission of outline proposal
April, 2020 – Registration with University College Dublin
May, 2020– Submission to the ethics committees of the hospital
June, 2020 – Submission of detailed proposal
July – August, 2020 – Collect data
September, 2020 – Submit thesis for examination
Specify the costs associated with this project, and any support funding that has been
requested or received: The summary should include all associated costs, with details of how figures
have been calculated.
Paper 100 sheets……………………………………………………………………. 7.00
Photocopying 10c per sheet X 100 sheets……………………………………… 10.00
Binding 3copies……………..……………………………………………………….. 85.00
Travel …………………………………………………………………………………110.00
All other expenses, self funded.
Signatures:
Applicant: Merlin James Paul
Supervisor: Lena Tyrell
Supervisor:
Date: 07.05.2019
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