A Compound for Use in Imaging Procedures Original Research Article

J of Nuclear Medicine Technology, first published online September 3, 2015 as doi:10.2967/jnmt.115.162404

A compound for use in imaging procedures

Original research article

Mulugeta Semework, Ph.D., Postdoctoral Research Scientist

Columbia University

Department of Neuroscience

1051 Riverside Drive, Unit 87

New York, N.Y. 10032

e-mails: [email protected] [email protected]

Tel: 678-362-3554, Fax: 646-774-7649

Sources of support: NINDS training grant from 2T32MH015174-35 (to Dr. Rene

Hen); Support from NEI grant 1 R01 EY014978-06 (to Dr. Michael E. Goldberg);

Supplement grant through NEI grant 3 R01 EY014978-06; Brain & Behavior

Research Foundation (NARSAD) 2013 Young Investigator Award; generous scan

time, technical and expert support from New York State Psychiatric Institute MRI

unit, PET Center at Columbia University Medical Center Department of

Radiology, Department of Radiology of the Center for Neurobiology and Behavior,

of Columbia University/Neurological Institute and the radiology department of NY-

Presbyterian Hospital.

Word count: 5073 (including references)

Short running title: Imaging compound

Abstract

Numerous research and clinical interventions, such as targeted drug deliveries or surgeries, finding blood clots, abscess, lesions, etc., require accurate localization of various body parts. Individual differences in anatomy make it hard to use typical stereotactic procedures that rely upon external landmarks and standardized atlases.

For instance, it is not unusual to make misplaced craniotomies in brain surgery. This project was thus carried out to find a new and easy method to correctly establish the relationship between external landmarks and medical scans of internal organs, such as specific brain regions.

METHODS This paper introduces an MRI, CT scan and X-ray visible compound

(composition) that can be applied to any surface and therefore provide an external reference point to an internal (eye-invisible) structure.

RESULTS Tested in non-human primates and isolated brain scans, this compound showed up with the same color in different scan types, making practical work possible. Conventional, and mostly of specific utility products such as contrast agents, are differentially colored or completely fail to show up, and are not flexible.

CONCLUSION This composition can be made with different viscosities, colors, odor, etc. It can also be mixed with hardening materials such as acrylic for different uses, such as for industrial/engineering objectives. Laparoscopy wands, electroencephalogram (EEG) leads, etc. could also be embedded with or surrounded by the compound for ease in 3D visualizations. A pending US patent

(IR# CU13187) endorses this invention.

Keywords— Structural MRI, CT-scan, X-ray, imaging compound, neurosurgery.

I. INTRODUCTION

Medical and engineering practices constantly employ the use of devices and methods for visualizing internal structures in humans, animals, machines, etc. Three very well established imaging methods, magnetic resonance imaging (MRI), computed tomography (CT) and X-ray are commonly employed.

Recently, integrated Positron emission tomography (PET) magnetic resonance

(PET/MR) systems have been getting attention and are currently being used in the clinic to measure motion with high temporal resolution (1) without additional instrumentation. The question still remains, how can one externally register a MRI,

CT, or X-ray identified internal body part with those visible to the naked eye? For instance, where should a surgeon make a precise 2 cm skin incision to remove a bone outgrowth which is only 1 cm wide, if that is all he needs?

With its increased ease, power and accessibility, especially the high resolution of T1-weighted structural images (2), MRI continues to be the choice medical imaging technique. There has been a growing interest in using this tool to study brain structure, function, development, and pathologies (3). However, unresolved technical and scientific difficulties, such as lack of means to scan and visualize certain objects, make it difficult to match up interest with success. These problems are critical especially when one considers surgery on vital structures such

as the brain, as anatomy differs despite similarities in organization and relative location with respect to each other.

There is variability between individuals in pattern of brain area folding, shape and size of cortical areas and relative locations (4). It is not uncommon to make a misplaced craniotomy when standardized atlases are used for localization of subcortical neural regions (5).

Since MRI is a non-invasive method that capitalizes on the complex mosaic across the cortical sheet (4), and since it permits the visualization of the neural structure of the brain in vivo (5), it is possible to solve much of this problem by taking individual MRIs pre-surgery and mapping structures of interest to an external marker and using established coordinates during surgery.

This invention aims at contributing to such a solution by expanding on a recent knowledge gained from preliminary research on non-human primates. It also builds upon an old method developed for expressing relationships between surface markers, such as tattoos on head skin and underlying major brain structures (6).

The previous (old) method mentioned above used a common practice of land marking to form a mathematical mapping with internal structures of interest. Skin tattoos (outside markers) were identified in MRI scans from vitamin E tablets affixed to the skin overlaying the tattoos. This posed three major problems for a wider use:

1) Vitamin E doesn’t show up equally and clearly in CT and X-ray scans and several

MRI sequences, such as T1, T2 and flairs. 2) The tablets are not flexible and sizable to affix to different external body parts which are not always straight or easily

accessible. 3) Not all external body parts that are accessible and straight allow reliable contact (stickiness) with the tablets.

The aforementioned problems call for a flexible, sizable and safe substance which can be used in, if not all, several MRI sequences and other scanning methods.

This paper introduces such a substance, an imaging compound which is not available in the market.

II. MATERIALS, METHODS AND PRELIMINARY RESULTS

To replicate common problems, such as Vitamin E and Gd showing up only on certain scans and conditions, data from both the starting development process and the final stages are presented in this and the main results section.

In short, the compound has been tested in monkey MRI, and fixed monkey brain CT scans and X-rays and it has been found to have well delineated radio density. It has not been clinically tested. For all experiments, there was no human subjects used and therefore no need for Institutional Review Board approval. The

Animal Care and Use Committees at Columbia University and the New York State

Psychiatric Institute (NYSPI) approved all protocols as complying with the guidelines established in the Public Health Service Guide for the Care and Use of Laboratory

Animals.

Figure 1 shows initial testing results in brief. The ingredients and the final mix were separately packed into different compartments of a small multi-pocketed plastic pouch. The compound (mix) is the only formulation which shows up more or

less equally and clearly in T1, T2 and T2 flair MRI scans (see Table 1 for parameters for all MRI sequences).

In general laboratory research practices, non-human primate skulls are routinely covered with a dental acrylic (cement), either to protect a craniotomy or to secure a head-posting structure. Being an ‘inert’ structure, the dental acrylic cannot be seen in any MRI scan. Using the compound however, its outlines can now be visualized. This allows the acrylic mound to be used in planning future surgeries, or following up of any process and objects inside it, or inside the brain (Figure 2).

By extension, the compound can be put over any body part, such as the skin over a patient’s chest, neck, etc. and the scan results can be used to plan interventions.

Since ultimately clinical utility will be the greatest target, the final MRI testing of this product was performed in a setting which resembles common medical practices in two ways. One: MRI scanning sequences with parameters used in patient evaluation procedures, including T1, T2, fast-spin echo (FSE), Fractional anisotropy, single-shot FSE (SSFSE), three-dimensional Fast Spoiled Gradient Echo

(3D-FSGPR), etc. were implemented. Two: a number of small vinyl tubes filled with the compound were glued to a plastic helmet (a swimming cap that mimics EEG caps, as shown in Figure 3), and the aforementioned scans were acquired. This is to demonstrate one possible use: a multi-purpose wearable landmark that can be imaged overlaying body parts (brain structures for instance).

Shown in Figure 3 are the results from an assortment of scans of the compound in a network of surgical tubes glued to a plastic cap covering a phantom/dummy brain. Note that the scans that do not show the compound clearly

are where diffusion and anisotropy are imaged, ones that are not the most widely used in the clinic. However, the seemingly negative results in Figure 3 were mostly because the parameters for all the scans have not been optimized at this stage.

Further refinement (of the MR methods and the chemistry of the compound) resulted in more positive results (subsequent figures).

The compound’s constitution was modified for the second round of testing, which aimed at further ascertaining the preliminary results and including other MRI sequences and scan types (CT and X-ray).

The main ingredients and their proportions (by volume) are: 1) distilled water/Betadine: 30- 45%, as solvents and bright T2-weighted MR images; 2) vitamin

E oil: 15-20%; 3) purified butter: 5-10%; 4) Olive Oil (slightly warmed) 5-10%; 5) other materials specific to project particulars (up to 15%).

Based on desired consistency and purpose, the percentage of the ingredients can be modified to make the compound. For instance, other ingredients (#5) can be as high as 45%. All of the images presented here used 45% solvent. Users are encouraged to experiment with the numbers to fit their special needs. A dedicated chemistry project (company) is anticipated to provide further help.

III. RESULTS

A. MRI

It is important for any imaging substance to encompass sequences because their use is going to continue at least for the foreseeable future.

The results for several clinical sequences (see discussion section for details) indicate that the compound has a great potential for use in clinical procedures. As can be seen in Figure 4, depending on which pulse sequences are used, the compound is clearly visualized with contrast and definition patterns that are similar to a T1 brain scan. Once again, the main feature of the compound is that it consistently shows up in just one color (white) in all tested sequences. Color

(brightness level) trends for contrast agents, gray or white matter and blood vessels are variable.

B. X-ray

Human body or other structures differentially attenuate x-rays and create shadows that are captured by x-ray-sensitive detectors. The transmitted fractions of the X-ray beams, captured by the detectors are now widely used to study objects hidden to the naked eye. They have been especially useful in medicine, such as orthopedic and pulmonary medicine. However, since transmissions and attenuations depend on opacity of imaged objects, it is still difficult to easily image and know the exact shape of objects that are relatively transparent, for instance skin compared to bone. If one can use a chemical such as the compound discussed here to differentiate soft tissue, then there will be no need for another kind of scan (MRI for instance) for further analysis and understanding of the object (body part) under study. For this reason, simultaneous X-ray images of the compound and other structures, such as a fixed monkey brain and a stainless steel rod were acquired

(Figure 5, see Table 2 for scan parameters). The scan results show that even under

low intensity image quality conditions, the compound can be visualized.

Understandably, it doesn’t show with the same intensity as stainless steel but it continues to be optimized for much more visibility.

C. CT scan

Following the success of x-ray imaging, instruments which recorded attenuation of x-ray beams (with the scanner rotating 180 degrees around the object) due to the imaged object, it was possible to get body cross-section images

(7,8). This method, called X-ray computed tomography (CT), has been widely used, but it also shares the same shortcomings discussed for MR and X-ray imaging. It too can benefit from a compound that can outline X-ray transparent objects. The images captured in a CT scanner show that the compound is visible and has well- defined edges (Figure 6, see Table 3 for CT scan parameters).

As there is a growing concern about radiation exposure and there are several approaches to reduce dose (8-10), the composition was scanned with both high and low dose conditions (Figure 7) and the results show that there are no critical and visible losses in image quality.

IV. DISCUSSION

The results presented here were obtained from experiments on a new imaging compound (composition) that shows up in MRI, CT and X-ray scans. In short, this compound was imaged after being filled in tubes, and also after being smeared over monkey acrylic head caps which are commonly used to house and stabilize recording chambers and head-post sockets. Its outlines can be visualized in various scans, and it made practical work successful. Its overall performance points towards a possible wide spread use as a marker for various subjects, whether it is human and primate body parts, or research tools. For instance, a sleep or epilepsy research clinic may use MRI safe EEG leads on a patient and may want to localize the leads to the actual underlying brain structures. MR images can be acquired after a dab of the compound is put on each lead, may be larger blobs marking suspect areas (epileptic foci for example) thus better associating structural images to experimental data. Conversely, the electrically conductive gel normally embedded in connector terminals of EEG, electrocardiogram and other leads, even surgical

(laparoscopy) and imaging wands, can be made with the compound, making 3D visualization possible without the need for constantly surface applying it.

It is anticipated that the compound will complement the use of internal contrast agents such as gadolinium (Gd) whose paramagnetic property has been extensively exploited despite its contraindication for patients with renal dysfunctions

(11). Since it is highly unlikely for a single-element-based substance to be the external surface equivalent of Gd, this compound is at the cross-roads of great utility,

price and functionality. Although it may need to be perfected for some specialized sequences, it has given encouraging results (see Figures 3 & 4) when tested in several MRI sequences discussed below.

T1 and T2 sequences are used for visualization and quantification of fat (T1) and water respectively (11-16). Both can further be refined by using fluid-attenuated inversion recovery (FLAIR) pulse sequences to suppress fluid signals, especially cerebrospinal fluids in brain scanning (11) and are used to localize lesions and edematous tissue.

MRA (MR angiogram, blood vessel imaging for arteries), and MRV (MR venography, blood vessel imaging for veins) sequences have clinical relevance and are routinely used. Pathological conditions in veins are investigated by MRV (17), although duplex ultrasound and CT scanning are also utilized and in identifying abnormalities such as obstructions (18). The same is true for arteries which are visualized best by sequences developed for oxygenated blood (MRAs).

The other alternative for investigating serious complications such as intracranial vascular diseases, intra-arterial catheter angiography, is slowly being replaced by angiographies using CT (CTA) or MRIs (MRA). This is because catheter angiography is invasive, requires in-patient admission, and has been associated with a 1-3% rate of neurological complications (19).

Another useful MR sequence is Diffusion Weighted Imaging (DWI). It is employed in diagnosing many pathologic conditions such as acute ischemia because it is highly sensitive to altered molecular motion of water (20). This sequence has been useful to discriminate various types of cancer such as

squamous cell carcinoma (21-23), other tumors, abscesses and autoimmune diseases such as Sjogren and Graves diseases (24).

The integrity of brain white matter is quantified and characterized by diffusion tensor imaging (25,26). This sequence is based on the principle that MRI is fundamentally imaging water protons based on movement of water molecules which is usually random (anisotropic) except in instances where they are bound by scaffolds such as fibers where they are forced into axial or longitudinal diffusion (27).

This sequence thus allows one to study brain connectivity in addition to integrity characterization. Accordingly, our composition can be incorporated into artificial fibers with predetermined architecture based on the need and application environment. This is in addition to and different from using the composition for building other structures, for instance artificial ceramic hips for purposes such as doing finite element analysis that simulate car crushes (material science applications). “Artificial fibers” specifically means viscous chemicals which have a locally non-random connectivity pattern giving directionality to water molecule movement during MRI.

One common practice to guide surgeries in humans, non-human primates and other animals, is registering the head to MR images in reference to a 3D position sensor. To do this, T1-weighted MRIs are routinely acquired (before surgeries are undertaken) with fiducial markers fixed to the head (headpost in animals). Such markers can be obtained from companies such as Brainsight (Rogue Research,

Quebec, Canada). During the surgical procedure, the fiducial markers are reattached, and using the MRI, specific brain structures are registered and targeted.

While this procedure is highly useful, it is sometimes possible to lose the marker signals in the initial scans, either due to the MRI sequence being not the right one, or possibly because of marker age.

For instance, when we acquired BRAVO (28) and T1 scans using the

Brainsight marker, we were not able to see the markers until we painted them with our compound. Moreover, unlike our flexible compound which can give a stable reference by providing a perfect contour of what it is put on, fiducial markers could cause errors. Chen and colleagues (29) have provided a detailed discussion of some of the potential complications. They indicate that errors could arise if the markers are not firmly attached to the imaged subject, if there is pressure on the markers during imaging, if they are not in the same exact locations in imaging and surgical procedures which could happen during patient transportation, surgical prepping, and head-clamp attachment. The authors also indicated other possible limitations such as targeting error could increase with depth based on the extrapolation distance from tracking spheres (markers). The problem of not putting pressure on the markers is sometimes difficult to solve, for instance in our primate scans where we use a custom-made coil which goes inside the stereotaxic apparatus and over the head.

As the product is more or less made of natural products, it is anticipated that it can be manufactured as a sterile product that can easily and safely be applied to exposed body parts including to exposed brain (dura to be specific). It can be made with different viscosities (consistencies), colors, odor, etc. Further testing and improvement of the composition and marketing negotiations are currently underway.

One encouraging recent development, the clinical testing of hybrid PET/MR systems (1,30), makes this composition an ideal candidate for further development and combined use. Moreover, anatomic, functional and molecular imaging and integration of biological data with medical imaging is becoming more an essential possibility (31). These advances call for matching technological advancements, such as this composition which has the potential to help in registering high-resolution internal anatomical images with external markers.

V. CONCLUSIONS

In brief, the great advantage of the product introduced here is that it has a well-defined boundary without evident artifacts, it is physically flexible, shows as the same color (white) in different scan types while common, and mostly of specific utility products such as contrast agents and Vitamin E tables are differentially colored, or do not show at all. Of course, future experiments and evaluations for this compound need to be completed with great care and understanding of possible artifact (interference) and stability behaviors, particularly those which could come with specialized formulations.

Financial Disclosure: NINDS training grant from 2T32MH015174-35 (to Dr. Rene

Hen); Support from NEI grant 1 R01 EY014978-06 (to Dr. Michael E. Goldberg);

Supplement grant through NEI grant 3 R01 EY014978-06; Brain & Behavior

Research Foundation (NARSAD) 2013 Young Investigator Award; generous scan time, technical and expert support from NYSPI MRI unit, PET Center at Columbia

University Medical Center Department of Radiology, Department of Radiology of the Center for Neurobiology and Behavior, of Columbia University/Neurological

Institute and the radiology department of NY-Presbyterian Hospital.

Acknowledgements: Heartfelt gratitude for Dr. Michael E. Goldberg‘s tireless support in this project. Special thanks to Andrew Gerber, Director, MRI Unit,

NYSPI and his wonderful staff; to Chaitanya R. Divgi, Director of the PET Center at Columbia University Medical Center Department of Radiology and his staff; to Stephen Dashnaw, Imaging Supervisor of the Center for Neurobiology and

Behavior, Department of Radiology, Columbia University/Neurological Institute and his staff; to Roy Thompson, Radiology manager at NY-Presbyterian Hospital; and Ron Katz and all of his Columbia Technology Ventures colleagues for all of their support.

Conflict of Interest: Dr. Mulugeta Semework and Columbia University have a patent application pending for the disclosed compound. No other author has a financial or proprietary interest in the material or methods mentioned.

Abbreviations:

2D: Two-dimensional

3D: Three-dimensional

EEG: electroencephalogram

PET: Positron emission tomography

GE: General Electric

NYSPI: New York State Psychiatric Institute

VI. References

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19. Jager HR, Grieve JP. Advances in non‐invasive imaging of intracranial vascular disease. Ann R Coll Surg Engl. 2000;82(1):1‐5. 20. Schafer J, Srinivasan A, Mukherji S. Diffusion magnetic resonance imaging in the head and neck. Magn Reson Imaging Clin N Am. 2011;19(1):55‐67. 21. Vandecaveye V, De Keyzer F, Dirix P, Lambrecht M, Nuyts S, Hermans R. Applications of diffusion‐weighted magnetic resonance imaging in head and neck squamous cell carcinoma. Neuroradiology. 2010;52(9):773‐784. 22. Friedrich KM, Matzek W, Gentzsch S, Sulzbacher I, Czerny C, Herneth AM. Diffusion‐ weighted magnetic resonance imaging of head and neck squamous cell carcinomas. Eur J Radiol. 2008;68(3):493‐498. 23. Kim S, Loevner L, Quon H, et al. Diffusion‐weighted magnetic resonance imaging for predicting and detecting early response to chemoradiation therapy of squamous cell carcinomas of the head and neck. Clin Cancer Res. 2009;15(3):986‐994. 24. Razek AA. Diffusion‐weighted magnetic resonance imaging of head and neck. J Comput Assist Tomogr. 2010;34(6):808‐815. 25. Chanraud S, Zahr N, Sullivan EV, Pfefferbaum A. MR diffusion tensor imaging: a window into white matter integrity of the working brain. Neuropsychol Rev. 2010;20(2):209‐225. 26. Viallon M, Cuvinciuc V, Delattre B, et al. State‐of‐the‐art MRI techniques in neuroradiology: principles, pitfalls, and clinical applications. Neuroradiology. 2015;57(5):441‐467. 27. Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage. 2002;17(3):1429‐1436. 28. GE_Healthcare. BRAVO. http://www3.gehealthcare.com/en/products/categories/magnetic_resonance_imaging/n euro_imaging/bravo. Updated June 20, 2012; Accessed August 1, 2015. 29. Chen AV, Wininger FA, Frey S, et al. Description and validation of a magnetic resonance imaging‐guided stereotactic brain biopsy device in the dog. Vet Radiol Ultrasound. 2012;53(2):150‐156. 30. Runge VM. Current technological advances in magnetic resonance with critical impact for clinical diagnosis and therapy. Invest Radiol. 2013;48(12):869‐877. 31. Huang HM, Shih YY. Pushing CT and MR Imaging to the Molecular Level for Studying the "Omics": Current Challenges and Advancements. Biomed Res Int. 2014;2014:365812.

VII. Figures

FIGURE 1. Imaging compound (“Mix”) and ingredients initial test procedure

and results. Arrows indicate the compound inside a 2 mm diameter surgical

tubing. Note how the commonly used Vitamin E tablet completely

disappears in T2 sequences. Gd: gadolinium. Ingredient #1: olive oil;

Ingredient #2: purified butter; Future ingredient #3: water.

FIGURE 2. MR imaging compound test results in various monkey brain

scans (panel titles). Note the white thin layer of the compound (top arrows)

showing on top of the dental acrylic (opaque mound indicated by lower

white arrows) lighting up in all scans. Right inserts (photographs) show

the actual dental acrylic implant in the monkey, the orientation marker (8

mm diameter plastic tube filled with the compound) and compound

placement procedures.

FIGURE 3. Preliminary imaging composition (mix) MRI test results in a

‘helmet- over-a-phantom’ brain scan. Arrows mark example locations in the

cross- sectional view of the “brain” where the composition is highly MR

visible. Almost all sequences show visible composition. Bottom right: A

dummy (phantom) brain wearing a plastic helmet with a network of vinyl

tubes filled with the composition.

FIGURE 4. MRI-scan results for imaging compound (mix, broken line

surrounding capital letters) in different sequence pulses (panel titles). A &

B are Formulations 1 & 2 of the compound mixed with dental acrylic. C:

Dental acrylic alone is MR invisible in all sequences. D & E: Formulations

1 & 2 of the compound without acrylic. All five preparations (A to E) were

put in 1 ml surgical syringes for stability during scans and ease in visual

comparisons.

FIGURE 5. X-ray results of imaging compound (mix). A: Stainless steel guide

tube (rod, 2 mm diameter). B & C are Formulations 1 & 2 of the compound

mixed with dental acrylic. D: dental acrylic alone. E & F: Formulations 1 & 2

of the compound without acrylic. All five preparations (B to F) were put in 1

ml surgical syringes for stability during scans and ease in visual

c o m p a r i s o n s . I n s e r t , G & H : 7 5 & 250 µm t h i c k m i c r o e l e c t r odes respectively.

I & J: Formulations 1 & 2 of the compound in 0.5 mm wide plastic guide-

tubes. The same scan is presented with increasing contrast from top to

the bottom panels.

FIGURE 6. CT-scan results of the imaging compound (mix). A: Stainless

steel guide tube (rod) with (2 mm diameter). B & C are Formulations 1

& 2 of the compound mixed with dental acrylic. D: dental acrylic alone. E &

F: Formulations 1 & 2 of the compound without acrylic. All five preparations

(B to F) were put in 1 ml surgical syringes for stability during scans and

ease in visual comparisons. G & H: 75 & 250 µm thick microelectrodes

respectively. I & J: Formulations 1 & 2 of the compound in 0.5 mm wide

plastic guide-tubes. As in Figure 5, image contrast increases from top to

the bottom panels.

FIGURE 7. High and low dose 3D CT-scan of the compound. A: Stainless

steel guide tube (rod, 2 mm diameter). B & C are Formulations 1 & 2 of the

compound mixed with dental acrylic. D: dental acrylic alone. E & F: 75

& 250 µm thick microelectrodes respectively. G & H: Formulations 1 & 2 of

the compound without acrylic. All five preparations (A, B, C, D, G & H)

were put in surgical syringes for stability during scans and ease in visual

comparisons. E & F: Formulations 1 & 2 of the compound in 0.5 mm wide

plastic guide-tubes.

VII. Tables

TABLE 1. Parameters used for MRIs

Series AT TE TR TI Th Mat Res Pix Mach Fig

T1 3D 4 34 0 1 256x 256 1 T2 97.27 5200 0 120x 256x 0.47x S* 120 256 0.47 Flair 120.64 10002 2200 224x 256 T2 FSE 105.76 10818 384x 2D 256 T1 flair 27.68 2300.06 970.54 2 320x 2 224 0.27x T2 flair 125.60 8000 2250 320x 512x 0.27 224 512 BRAVO 3D 4.10 9.36 450 384x 256 T1 FLAIR 16.81 3000.01 1000 288x 0.49x 3 5 192 0.49 DWI 80.8 224x 256 T2 FSE 2D 8000 128x 0.94x DTI 80.4 0 4 128 256x 0.94 256 SSFSE 40.10 953.78 5 288x 512x 0.43x D† 192 512 0.43 SAG 3D 3D 2.55 6.32 500 1 0.98x FSPGR 128x 256x 0.98 Fractional 2D 80.4 8000 0 4 128 256 0.94x anisotropy 0.94 BRAVO 3D 2.55 6.32 500 1 0.98x 4 0.98 T1 FLAIR 24 2300 320x 140x 0.44x 2D 2 244 140 0.57 T2 FLAIR 120 8000 2250 320x 140x 244 140 MRA 3D Out of 23 1.2 256x 140x phase 192 105 0.55x MRV 2D Min Min 1.5 256x 140x 0.55 192 105

AT = acquisition type; TE = echo time (ms) ; TR = repetition time (ms); TI = inversion time (ms); Th = thickness (mm) ; Mat = acquisition matrix; Res = resolution; Pix = pixel spacing (ms); Mach = machine; Fig = Figure

S*: 1.5 T GE Medical Systems Signa Excite Scanner D†: 3-T GE Medical Systems Discovery MR750 scanner

TABLE 2. Parameters used for X-ray (see Figure 5)

kVp I Modality Filter DP Res Fov E Px ET (mA) (dGy* (mAs) (ms) cm*cm) 62 101 Bone Multiple/ 0.09 865x 173x 1.61 0.19x 16 densitometry Cu 1136 227 0.19 (DX) kVp = kilovolt peak; I = x-ray rube current; mAs = milliamperes; Cu = copper; DP = Image area dose product; dGy = deciGray; Res = image resolution; Fov = field of view dimensions; E = exposure; Px = imager pixel spacing; ET = exposure time

TABLE 3. Parameters used for CT scans

Scan Total Tota Scan kV mAs ref CTDvol DLP TI cSL Fig type delivered l mGy mGy (s) (mm) ure (mAs) DLP *cm (mG y*c m) High 1628 190 Topogram 120 30 mA 5.3 0.6 dose HR 120 9.09 190 0.5 6/7 Low 854 89 Topogram 120 35 mA 5.3 0.6 7 dose HR 50 3.80 89 0.5 mAs = milliampere seconds (applied milliamperage); DLP = dose length product; Total DLP = DLP value of the entire examination (estimated radiation exposure); kV = tube potential; ref = quality reference milliamperage; CTD = computed tomography dose index; mGy*cm = dose area product; TI = rotation time; cSL = section collimation