Automatic Calibration of MiCES Modules

1. Craig Dowell University of Washington MS Presentation November 20, 2009 Automatic Calibration of MiCES Modules

2. Development of Small Animal PET Systems the micro crystal element scanner (MiCES) Supported by NIH grants R01-EB002117 (Lewellen), R24-CA88194 (Lewellen), R21/R33- EB0001563 (Miyaoka), and P01-CA42045 (Krohn). Automatic Calibration of a Small Animal PET System Supervised by Robert Miyaoka Joseph Rothberg Research Associate Professor of Radiology Professor of Physics University of Washington University of Washington Automatic Calibration of MiCES Modules

3. MiCES Automatic Calibration November 2009 Outline of the Talk • What is PET • Some fundamental limitations of PET • How PET is used • PET calibration • Some interesting or surprising results • Lessons learned • Short Q&A

4. MiCES Automatic Calibration November 2009 What is PET? • One of a family of tools • Radiograph • Your average, everyday X-ray picture • Computed Axial Tomography (CAT or simply CT) • Collimated X-ray “slices,” contrast enhanced • Magnetic Resonance Imaging (MRI) • Proton spins are manipulated and detected • Positron Emmision Tomography (PET) • Β-decay of radioactive tracers are detected. • Tools can be used together • PET/CT Fusion (best of both worlds).

5. MiCES Automatic Calibration November 2009 What is PET? • PET measures presence of radioactive tracers, not physical structure – metabolism • Metabolically active compounds are created with radioactive elements (often 18F) • To study glucose metabolism need to look at dextrorotatory glucose; • Create deoxyglucose by replacing hydroxyl of glucose with H (which inhibits further metabolism) • Create fluorodeoxyglucose by replacing H with F • If 18F is used, get tracer with half-life of 110 min called 18F-FDG • When 18F decays to 18O it combines with an available H to form the missing hydroxyl • Then metabolized normally and safely

6. MiCES Automatic Calibration November 2009 What is PET? • Tracer compounds are injected into subjects • Tracer compounds are metabolized in the body as if they were the compounds of interest • In areas of greater or lesser metabolism, the tracer compounds accumulate in different amounts • Eventually the radionuclides in the tracer compounds decay and emit positrons • Positrons annihilate and emit gamma rays in (essentially) opposite directions

7. MiCES Automatic Calibration November 2009 What is PET? • Gamma ray detectors surround a subject • Coincidence of gamma ray detection events implies a “line of response” to originating annihilation event • 3-D images are constructed from many LORs • More LORs coming from “voxel”means “brighter” point in image • Can infer greater rate of metabolism at brighter points • Can infer lesser perfusion fromdimmer points

8. MiCES Automatic Calibration November 2009 What is PET? • Gamma rays are detected by combination of Scintillator Crystals and Photomultiplier Tubes • When gamma ray photon enters a scintillator crystal it loses energy through photoelectric effect and Compton scattering (energy too low for pair production) • Results in visible or UV radiation (a flash of light) • Light intensity varies with deposited energy • Light is coupled to a Photomultiplier Tube (PMT)

9. MiCES Automatic Calibration November 2009 What is PET? • Light strikes photocathode of PMT which emits electrons • Electrons area accelerated onto dynodes which generates secondary electrons • Results in an avalanche effect that can be processed by system electronics

10. MiCES Automatic Calibration November 2009 What is PET? • PET scanners may use Position Sensitive PMTs (PSPMTs) • Miniaturized PMTs packaged in an array (6 x 6 in MiCES)

11. MiCES Automatic Calibration November 2009 What is PET? • Real PET scanners use many thousands of scintillator crystals and hundreds of PSPMTs

12. MiCES Automatic Calibration November 2009 What is PET? • Hits can be histogrammed, resulting in familiar shapes (here for Na-22).

13. MiCES Automatic Calibration November 2009 Limitations of PET • Positrons are emitted into matter (tissue) • They deposit energy into surroundings • Critical energy is 92 MeV (cf. 630 KeV) in water so radiation loss not an important mechanism in PET • Positrons move through Coulomb fields and undergo accelerations. • Follow tortuous path, dissipating energy • Combine with electron to form positronium and annihilate producing two 511 KeV photons

14. MiCES Automatic Calibration November 2009 Limitations of PET • Positron annihilation is source of detected photons, not emission – not at same place • Distance positron travels called “positron range” • Depends on medium and radionuclide • A fundamental limit on PET resolution

15. MiCES Automatic Calibration November 2009 Limitations of PET • Mean positron rangefor radionuclides • 18F: 0.6 mm • 11C: 1.1 mm • 13N: 1.5 mm • 15O: 2.5 mm • Get differentresolutions dependingon tracer requirements

16. MiCES Automatic Calibration November 2009 Limitations of PET • Positrons are not stationary when they annihilate. • Conservation of momentum dictates photons not emitted precisely 180o apart • Called non-collinearity error • Another fundamental limit to PET resolution

17. MiCES Automatic Calibration November 2009 Limitations of PET • PET needs a line of response between detectors to reconstruct an image • Non-collinearity errorscause selection of incorrect lines of response • Errors on the order ofmm • Dominates positron range as source of uncertainty in larger scanners (s=rθ)

18. MiCES Automatic Calibration November 2009 Limitations of PET • Just like the positrons, the annihilation photons are emitted into matter • Photons scatter and cause errors • Scatter events reduce photon energy • PET scannersdiscard scatteredphotons (limited bydetector calibration)

19. MiCES Automatic Calibration November 2009 How is PET used? • PET can “see” high concentrations of tracer • Cancerous cells generally have higher than normal metabolism and accumulate more tracer; • Cancer indicated by a “bright” area in PET. • PET can “see” low concentrations of tracer • Lower than normal perfusion blocks accumulation of tracer; • Blockage in coronary artery indicated by a “dim” area in PET.

20. MiCES Automatic Calibration November 2009 How is PET used? • Diagnosis and Treatment of Cancer • Detection of cancer before physical changes are visible in CT/MRI • Assess effectiveness of treatment plan. • Example CT PET PET/CT Fusion Superclavicular Lymphoma from Cedars-Sinai (csmc.edu)

21. MiCES Automatic Calibration November 2009 How is PET used? • Perfusion Studies • Detection of heart attack, and determination of extent of damage; • Assess effectiveness of treatment plan (bypass/stent). • Example • Radiotracer associated with blood; • Areas of cardiac walls with low perfusion show as dim (green arrows). Myocardial Infarction – Adapted from heartandmetabolism.com

22. MiCES Automatic Calibration November 2009 How is PET used? • Neurological Studies • Detection and diagnosis of Alzheimer’s Disease through changes in glucose metabolism. • Example • Measure glucose metabolism in brain; • Cognitive impairment varies with glucose metabolism. From UC Berkeley News (berkeley.edu)

23. MiCES Automatic Calibration November 2009 How is PET used? • Biodistribution Studies (pharmacology) • Radiolabel new drugs; • Introduce and measure uptake. • Example related to growthfactor • Drug labeled with 11C; • Injected into volunteer; • After 40 minutes, noticeaccumulation in • Liver; • Urinary bladder; • Kidneys. From Journal of Nuclear Medicine

24. MiCES Automatic Calibration November 2009 How is PET used? • Ethical problems with experimentation on people • PET scanners are scaled for people • Small animal PET scanners allow for experimentation on lab animals • Addresses basic resolution problems and many simple issues of scale

25. MiCES Automatic Calibration November 2009 My Favorite PET Scanner • The Micro Crystal Element Scanner (MiCES) small animal PET scanner developed at UW IRL • The subject of the automatic calibration effort • Embedded system with “Rabbit” processors, FPGAs and ASICs

26. MiCES Automatic Calibration November 2009 MiCES Calibration • PET Systems are made up of thousands of components • Components respond differently within expected variations (tolerances) • Eventually we want to make cuts on energy and timing of hits to isolate non-scattered annihilation photons • Allows for most accurate LORs and clearest images. • Calibration is about enabling accurate cuts

27. MiCES Automatic Calibration November 2009 MiCES Calibration • Fifteen “knobs” to turn per electronics board and calibrate the system • Aligning the positions of photopeaks enables more precise cuts on energy • One high voltage setting shared between two PSPMTs per board • Four amplifier gain settings for PMT output signals must be adjusted • Constant Fraction Discriminator setting allows discarding uninteresting events (noise) • Fine-grain timing information comes from TAC which must be separately calibrated (resistive ladder) • Want to arrange main features of histograms to occur in same place over many different modules.

28. MiCES Automatic Calibration November 2009 MiCES Calibration • Feedback is via histograms • Implemented in FPGA; • Available to Rabbit processor; • PSPMTs divided into four quadrants; • Edge pixels not accumulated; • Single histogram per quadrant; • 256 energy bins per histogram. • Timing information in fifth “quadrant”; • 32 bins of fine grained start time.

29. MiCES Automatic Calibration November 2009 MiCES Calibration • First step is to adjust HV (gain for PSPMT 0) • Second step is to adjust ASIC gain for PSPMT 1 • Third, fourth steps are to set CFD threshold for PSPMT 0 and 1 • Fifth, sixth steps are to set TDC offset and gain for PSPMT 0 and 1 • Final step is to write calibration results to flash • Results are automatically loaded on restart

30. MiCES Automatic Calibration November 2009 Calibration • Before and after energy histograms

31. MiCES Automatic Calibration November 2009 Calibration • Before and after time histograms

32. MiCES Automatic Calibration November 2009 Interesting Results 1 • Funny shaped photopeak; • Backscatter peak larger than photopeak.

33. MiCES Automatic Calibration November 2009 Interesting Results 1 • Why? • Each PSPMT is an array of miniature PMTs; • Gain of each PMT can vary by more than 30% (source Hamamatsu). • Scintillator crystal characteristics (light output) varies acrossthe 484 crystals • Variations in bonding of crystalsto PMT (delamination)

34. MiCES Automatic Calibration November 2009 Interesting Results 1 • Why? • Three different photopeaks from three different anodes?

35. MiCES Automatic Calibration November 2009 Interesting Results 1 • Why? • Orthogonal display shows phenomenon clearly; • Notice gain drop overabout one sixth of PMTwidth in saggital slice; • Six X-direction anodesper PMT.

36. MiCES Automatic Calibration November 2009 Interesting Results 1 • Implications • Can’t just look for highest count and assume that is photopeak – it might be a backscatter peak; • Differences between quadrants within one PSPMT are often greater than between different PSPMTs; • If looking for unscattered annihilation photons by filtering on 511 KeV photons, you want to look for hits around the photopeak – but positions of photopeaks have 30% tolerance; • Can do calibration on end-to-end system using map files to come up with compensation values since map files have pixel resolution; • Not possible with current FPGA histogrammer. • It’s hard to tell where the cut value is between a good module/PSPMT and a bad one.

37. MiCES Automatic Calibration November 2009 Interesting Results 2 • Delamination of Crystals • It is suspected that high temperatures in the lab caused delamination of crystals; • crystal-map tool shows reduced hit counts quite clearly.

38. MiCES Automatic Calibration November 2009 Interesting Results 3 • Human eyes are good when in doubt • What is to be made of this histo? • Perhaps a photopeak at bin 24, another photopeak at bin 40 corresponding to another anode, and reinforcing backscatter peaks at bin 7? • What would scanner energy filters make of this spectrum? • Could be sorted out withend-to-end calibration –does that exist? • Is this module good orbad? This may confuse thecalibration code and is why “manual override” is implemented.

39. MiCES Automatic Calibration November 2009 Interesting Results n • There are many “novel” histograms laying around in the system; • When I started this project, I went through many of them to try and get my bearings and was often completely baffled; • I think many of the odd histograms were due to various failures in the system. Cables are notoriously fickle; • I tried to make the calibration code fairly robust, but I am (and my code is) still surprised by what sometimes happens.

40. MiCES Automatic Calibration November 2009 Lessons Learned • The hardest part was understanding why so many histograms were so “oddly” shaped; • Spend time up front writing tools and scripts for gathering, reducing and presenting data – it is well worth it; • Looking at lots of histograms with human eyes is important – run code on as many different modules as possible, as soon as possible; • Don’t be afraid to throw things away if they aren’t working out.

41. MiCES Automatic Calibration November 2009 Discussion Short Q and A