Monte Carlo Demonstration of Small Animal in-vivo Functional And Anatomical Imaging With Neutrons

1. Monte Carlo Demonstration of Small Animal in-vivo Functional And Anatomical Imaging With Neutrons David C. Medich, Ph.D., CHP

2. Goals of this Presentation To provide a justification as to why we could use a new clinical and biomedical imaging tool. To discuss how neutrons can be used to obtain an in-vivo biological image that contains functional and anatomical information. NOTE: focus here is on a small animal model. To present Monte Carlo simulated results for: Basic neutron images comparing quality both with and without scatter contributions, S/N ratio of different tissues and materials relative to water, S/N ratio of tumors relative to their normal tissue counterpart, S/N ratio of B-10 and Gd-157, to determine the concentrations needed to obtain a useful functional image in a mouse model.

3. Limitations: Current Technology Technologies such as f-MRI, PET, and SPECT have been very successful in identifying changes in tissue metabolism and function, but these technologies have limitations... • Poor spatial resolution : fMRI (2-3mm), PET (3-5mm), SPECT (5-10mm), • fMRI – poor temporal resolution, • Little to no anatomical imaging info is obtained from the technology • PET – requires on-site (or close proximity) cyclotron to produce positron emitters with very short half-lives, • SPECT – isotopes produced at very limited number of foreign reactors. A temporary shutdown of one of these reactors leads to clinical isotope shortages...

4. Possible Role of Neutrons in Functional Imaging...

5. Neutron Radiography General Advantages: – why neutrons? • Neutrons interact directly with the atomic nucleus (unlike photons which interact with atomic electrons). • Neutrons therefore have different reaction rates for isotopes of the same element. • Neutrons also have a high dynamic range of interaction cross-sections. • neutron radiography, which our technique is based, has very high spatial resolution and efficiency. • Kardjilov, for example, used a 10 mm Gd2O2S(Tb) screen and reported a 90% detection efficiency with a spatial resolution of 25 mm.(1) 1. N. Kardjilov et al. Nucl. Instr. and Meth. A 651 95-99 (2011)

6. Neutron Radiography Potential Clinical Advantages Neutrons interact readily with hydrogen, and nitrogen (and to a lesser extent carbon and oxygen) compared to many other materials. Therefore, Neutrons are very sensitive to local changes in a tissue’s H, C, O, N content. This is important because, as we know from MRI, changes in hydrogen content enables us to anatomically differentiate and image soft tissues. And, certain stable and non-toxic isotopes are much more opaque to neutrons than lead is to diagnostic x-rays! Therefore, these isotopes could be used with neutrons as a very effective contrast agent.

7. Advantages of Neutron Imaging

8. Advantages of Neutron Imaging Here is a quick summary of the thermal neutron absorption in B-10 and Gd-157 as compared typical x-ray photon absorption in lead...

9. Advantages of Neutron Imaging Identifiable Tumors Neuron Radiography X-ray Radiography Comparison of raw tumor imaging capabilities in neutron radiography and x-ray radiography: The top images demonstrate that native neutron radiography has basic tumor detection capabilities. Image From: Brown and Parks, “Neutron Radiography in Biologic Media”, Am. J. Roentg106, 472 (1969)

10. Advantages of Neutron Imaging Comparison between (a) histology and (b) Neutron Capture Radiography of a 70µm thick liver tissue sample with liver metastases after infusion of BPA. From: Wittig, A., J. Michel, et al. (2008). "Boron analysis and boron imaging in biological materials for Boron Neutron Capture Therapy (BNCT)." Critical reviews in oncology/hematology 68(1): 66-90.

11. Advantages of Neutron Imaging Neutron Image X-ray Image

12. Advantages of Neutron Imaging From: Metzkeet. Al. “Neutron computed tomography of rat lungs” 2011 Phys. Med. Biol. 56 (2011) N1–N10

13. Advantages of Neutron Imaging Potential Clinical Applications for Anatomical Imaging: Both native and functional tumor detection have been demonstrated. Possible identification of early-stage osteosarcoma in both trabecular and compact cortical bone. Ability to image near or through metallic implants or pacemakers. Also could assess blood flow around an aneurism embolization coil or vascular stent. And assess the status and function of mechanical and cosmetic implants. More importantly, when combined with a neutron-opaque imaging agent, neutron imaging could be an excellent alternative to current functional imaging modalities (i.e. Neutron Functional Imaging)...

14. Functional Neutron Imaging • We are investigating B-10 and Gd-157 labeled contrast agents to provide high contrast between diseased and normal tissue and with spatial resolutions orders of magnitude better than PET, SPECT, or f-MRI. • We call our technique Contrast Enhanced Neutron Imaging (CENI) • In addition to high spatial resolution in functional imaging, CENI also could offer anatomical information • CENI would not use any radioactive materials. • No need to inject radioactive materials into patient. • No reliance on foreign nuclear reactors for SPECT isotopes. • No need for on-site cyclotrons for PET isotopes. • Lower patient radiation exposures.

15. Functional Neutron Imaging A Picture is worth a Thousand Words... Depiction of how spatial resolution affects the ability to identify disease. Here, an ischemia is located on the distal end of a mouse heart which is represented at spatial resolutions of 30m, 250m, and 2mm. NOTE: UML is in the process of upgrading its CCD radiography camera. The resolution of the new camera system (so far) appears to be around 80 mm.

16. Problems with Biological Imaging So, why haven’t we been using this ! Previous biological imaging research with neutrons found that the image quality obtained when imaging biological organisms thicker than ~1 mm is extremely poor . • A Neutron also pose a greater biological risk to tissue relative to an x-ray photon • concern exists that biological neutron radiography could lead to potentially high radiation exposures to the patient… • Ultimately, many of the interesting interaction mechanisms between neutrons and tissue also cause difficulties when trying to obtain a good biological image... • We will show that neutron energy selection is very important... • And, that the interaction mechanism with hydrogen causes problems for biological imaging of large objects.

17. Neutron Energy Selection I am focusing my research on small animal functional imaging using thermal neutrons. Most neutron imaging systems use thermal neutrons but, to image large biological objects, we will require energetic neutrons. Why? • Present tech. can’t functionally image small animals! • The mouse is the most studied, characterized, and cheapest bio-model to use (also the quickest to obtain results due to life-span). • This also is the easiest way to being implementing CENI.

18. Problems with Biological Imaging • Neutron Radiograph of a Mouse cranium using a 16:1 cadmium coated bucky-grid. • X-ray radiography image of the same mouse cranium. The grid ratio used to form this image was not specified but is assumed to be 16:1. Let us examine closely the neutron interaction with hydrogen… Image From: Brown and Parks, “Neutron Radiography in Biologic Media”, Am. J. Roentg106, 472 (1969)

19. Neutron Scatter with Hydrogen… Comparison of X ray and Thermal Neutron Interaction Probabilities... Photon Cross Section Neutron Cross Section • While photoelectrons will not degrade image quality, scattered neutrons will strongly degrade image quality…

20. Research Hypotheses Hypothesis #1: The limitations observed with biological neutron radiography predominately are due to the inability to adequately remove hydrogen scattered neutrons from image formation (anatomical imaging). Hypothesis #2: That 10Boron and 157Gadolinium have sufficiently high absorption cross-sections for use as a non-radioactive contrast agent for functional neutron imaging studies (functional imaging).

21. Scatter vs. Image Quality • We tested our first hypothesis through a series of basic computer simulations using the MCNP5 radiation transport program. • MCNP5 is a software package developed by Los Alamos National Laboratories. • It is used to model coupled neutron / photon / electron transport through material and their resulting interactions. • Images were formed using the FIR Radiography fluence tally. • We included S(,) transport corrections for the thermal motion (vibration/rotation) of hydrogenous molecules.

22. Scatter vs. Image Quality First: We performed a simple Monte Carlo contrast analysis of four major tissues and materials common in medical imaging to see if we could natively differentiate anatomical tissues with neutron biological imaging (non-optimized). muscle bone adipose water

23. Scatter vs. Image Quality • We analyzed muscle, cortical bone, adipose tissue, water, and air contrast from thermal neutrons (0.025 eV) . • Two images were obtained: one with neutron-scatter contributions to image formation and one without neutron scatter contributions. • We used an image resolution of 1mm2 • Each material was modeled as being a rectangle with a thickness of 1 cm. • No special image processing was done on the resulting image.

24. Scatter vs. Image Quality 1 RESULTS:

25. Scatter vs. Image Quality Resulting contrast differences between muscle, bone, adipose tissue, water, and air under conditions of complete neutron scatter removal.

26. Scatter vs. Image Quality Next: We simulated (again using MCNP5) a basic arm phantom consisting of: muscle, bone, and an added bone-fracture. Representation of the Monte Carlo simulated phantom.

27. Scatter vs. Image Quality • We modeled muscle, bone, and a bone fracture: • Muscle OD=5cm, • bone OD=2cm, • Fracture 1mm thick through bone center. • Again, (non-optimized) images were simulated in MCNP environment both with-and without image contributions from scattered neutrons • Again, used a receptor grid resolution of 1mm2 (not all that important) • Again, no special image processing was done on the resulting image.

28. Scatter vs. Image Quality B: Scatter Removed A: Scatter Included Comparison of images formed with scattered neutron contributions and without…

29. Scatter vs. Image Quality Neutrons of various energies Scatter removed…

30. Scatter vs. Image Quality Neutrons of various energies Scatter included…

31. Tissue Contrast: S/N • Most recently, we used MCNP to quantify the neutron fluence needed to obtain a suitable signal to noise ratio in a small animal model for functional and anatomical imaging. • Our goal is to quantify object tissue and tracer contrast (and, to an extent the dose equivalence delivered per image). • We analyzed: • Different anatomical tissues contrasts relative to water. • Tumor cell contrast vs. their normal cell counterpart. • The required boron-10 concentration in tissue needed to act as a suitable contrast agent in functional imaging. • The required gadolinium-157 concentration in tissue needed to act as a suitable contrast agent in functional imaging.

32. Tissue Contrast: S/N Note: the dose equivalence from neutrons of fluence 0 also is presented as a benchmark. This value was obtained using the 10CFR20 flux to dose conversion factors.

33. Tissue Contrast: S/N For this experiment, we simulated a basic 3 cm thick phantom in the MCNP code (similar to the thickness of a large mouse); the Monte Carlo methodology used was similar to that used for the other studies... 1. Various target tissues (and materials) were modeled in a water phantom with tissue thicknesses varied between: 0.1mm & 10mm. These target tissues studied included: Adipose Muscle Soft Tissue Bone (cortical) Water air

34. Tissue Contrast: S/N 2. Also, tumor cell types were compared to their normal cell counter-parts at various target thicknesses (0.1-10mm): Carcinoma to soft tissue Melanoma to skin / soft tissue Sarcoma to muscle tissue Squamous lung to normal lung tissue 3. Lastly, B-10 and Gd-157 concentrations were simulated as contrast agents in a water phantom. Again, target tissues were modeled between 0.1mm and 10 mm. [B-10]: Concentrations of B-10 simulated were: 10, 50, 100, 300, 500, 700, 1000, 2000 g / g. [Gd-157]: Concentrations of Gd-157 simulated were: 1, 5, 10, 30, 50, 80, 100, 200 g / g.

35. Side Note: What Can I “See”? S/N = 2, Background (1 sigma) 1 * (background & signal) S/N = 2 2 * (background and signal) S/N = 5 3 * (background and signal) S/N = 1 Note:S/N = 5 required for single pixel contrast (Rose Criteria)

36. Tissue Contrast RESULTS: Differentiation of Tissue vs. Water

37. Tissue Contrast

38. Tissue Contrast

39. Tumor Contrast RESULTS: Differentiation of Tumor vs. Normal Tissue

40. Tumor Contrast

41. Boron Contrast RESULTS: Contrast from Various Boron-10 Concentrations Yellow: B-10 concentration presently used in 10BPA BNCT Red: B-10 boron-carbide nanoparticle concentration used by Mortensen for BNCT

42. Boron Contrast Yellow: B-10 concentration presently used in 10BPA BNCT Red: B-10 boron-carbide nanoparticle concentration used by Mortensen for BNCT

43. Gadolinium Contrast RESULTS: Contrast from various Gd-157 concentrations Yellow: Gadolinium concentration presently for Gd-DTPA MRI

44. Gadolinium Contrast Yellow: Gadolinium concentration presently for Gd-DTPA MRI

45. Dose Eqvt. for 0.3 mm contrast Summary: Dose Required for 0.3mm slice identification for various S/N Ratios (B-10)

46. Dose Eqvt. for 0.3 mm contrast Summary: Dose Required for 0.3mm slice identification for various S/N Ratios (Gd-157)

47. Conclusions With proper scatter-removal, neutrons can obtain usable anatomical information in a mouse model This information would be complementary to that obtained using x-ray, CT, and MRI. All tissue types can be imaged with this technique and with minimal radiation exposure to the mouse CENI also has been shown to be able to natively differentiate tumors from their normal cell counterpart!

48. Conclusions More importantly, neutrons can be used with B-10 or Gd-157 to obtain metabolic and functional imaging information in a mouse model: Our technique would have spatial resolutions better than 10x that presently obtained with PET/SPECT and fMRI. It would require quantities of B-10 and Gd-157 that are biologically safe and in quantities used in present medical procedures. CENI can be used with any type of functional imaging study presently performed. From a safety perspective, CENI also is expected to provide lower (or at least equivalent) radiation exposures since no radioactive materials are used.

49. Acknowledgements I wish to thank my collaborators: Dr. Andrew Karellas Director of Radiological Physics Professor of Radiology University of Massachusetts Medical School Dr. Peter Gaines Assistant Professor of Biology University of Massachusetts Lowell And my research assistants, who have or are working on this project: Blake Currier Daniel Cutright, Ph.D.

50. Questions?