1. Design and simulation of micro-SPECT: A small animal imaging system Freek Beekman and Brendan Vastenhouw Section tomographic reconstruction and instrumentation Image Sciences Institute University Medical Center Utrecht

2. PRESENTATION OUTLINE Introduction in tomography Tomography with labeled molecules (“tracers”). Principles of SPECT Image reconstruction Ultra-high resolution SPECT for imaging small laboratory animals => Need for high resolution gamma detectors

3. Cross-sectional images of the local X-ray attenuation in an object are reconstructed from line integrals of attenuation (“projection data”) using a computer Computed Tomography Computed Tomography 1979: Hounsfield and Cormack share Nobel Prize…..

4. Why Computed Tomography ?

5. We are curious how we, other people, animals, etc, look inside…... … but we don’t like to (be) hurt !

6. Examples of Tomography Anatomy X-ray Computed Tomography X-ray Computed Tomography Magnetic Resonance Imaging (MRI) Magnetic Resonance Imaging (MRI) Molecule distributions Positron Emission Tomography (PET) Positron Emission Tomography (PET) Single Photon Emission Computed Tomography (SPECT) Single Photon Emission Computed Tomography (SPECT)

7. X-ray CT: Cross-sectional images of X-ray attenuation provide knowledge about anatomy

8. We are also curious how organs... …..are functioning in vivo

9. Molecular imaging Emission tomographs (PET and SPECT) are suitable in vivo imaging of functions (blood perfusion, use of oxygen and sugar, protein concentrations)Emission tomographs (PET and SPECT) are suitable in vivo imaging of functions (blood perfusion, use of oxygen and sugar, protein concentrations) Uses low amounts of injected radiolabeled moleculesUses low amounts of injected radiolabeled molecules

10. PET and SPECT imaging enables mapping of of radiolabeled molecule distributions What area in the brain is responsible for a task?

11. SPECT: Single Photon Emission Computed Tomography Patient is injected with a molecule labeled with a gamma emitter. For determination of travel direction detectors are equipped with a lead collimator.

12. To form an image, the travel direction of detected photons must be known. The collimator selects  -quanta which move approximately perpendicular to the detector surface. Detector > IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII <= Lead collimator Collimated gamma-camera

13. Slices are reconstructed (Filtered Back Projection (FBP) or Iterative Reconstruction). Resolution in humans: 6-20 mm Resolution can be much better in small animals (< 1 mm) <= Slice of Tc-99m distribution Slice of SPECT image => Slice of SPECT image =>

14. SPECT Technetium-99m Cardiac Perfusion Image

15. IMAGE RECONSTRUCTION FROM PROJECTIONS Analytical (Radon Inversion) Discrete (Statistical) Methods

16. p = M a + n + b p = M a + n + b p j = M ji a i + n j + b j a i = activity in voxel i p j = projection data in pixel j b j = back-ground in pixel j (e.g. scatter) n j = noise in pixel j M ji = probability that photon is emitted in voxel I is detected in pixel j. Attenuation, detector blur and scatter can be included. Attenuation, detector blur and scatter can be included. Estimate a from above equation SPECT reconstruction problem

17. SPECT reconstruction matrix SPECT reconstruction matrix is complicated by Detector blurring Detector blurring Attenuation Attenuation Scatter Scatter 3D reconstruction 3D reconstruction

18. Simulation (or “re-projection”) Iterative Reconstruction illustrated Iterative Reconstruction illustrated Object space Estimatedprojection Measured projection projection “Error” “Compare” e.g. - or / Projection space Currentestimate “Back- projection” Object error map Update

19. 0 iterations10 iterations30 iterations60 iterations Example iteration process: ML-EM reconstruction brain SPECT ML-EM reconstruction brain SPECT

20. line integral model accurate PSF-model

21. Small animal molecular imaging using single photon emitters (micro-SPECT)

22. Expected contribution of micro-SPECT to science Partly replacement of sectioning, counting and autoradiography. Partly replacement of sectioning, counting and autoradiography. Reduction of number of animals required Reduction of number of animals required Dynamic and longitudinal imaging in intact animals Dynamic and longitudinal imaging in intact animals Contribution to understanding of gene functions Contribution to understanding of gene functions Acceleration of pharmaceutical development Acceleration of pharmaceutical development Breakthroughs in areas like cardiology, neurosciences, and oncology Breakthroughs in areas like cardiology, neurosciences, and oncology Extension of micro-SPECT technology to clinical imaging (~2006) Extension of micro-SPECT technology to clinical imaging (~2006)

23. In Vivo Nuclear Microscopy (Eur J. Nucl. Med and Mol. Im., in press) Golden micro-pinholes Golden micro-pinholes => Super High Resolution SEM image of gold alloy pinhole

24. 20 min. acquisition 20 min. acquisition arrows indicate locations parathyroid glands ~1 mm Microscopic slide Mouse thyroid I-125 pinhole image ~

25. Pinhole imaging geometries for small animal imaging SPECT (micro-SPECT)

26. Spatial resolution clinical SPECT ~ 15 mm Spatial resolution current small animal SPECT and PET: 1.0-2.5 mm Micro-SPECT= dedicated small animal SPECT. with resolution 0.2-0.4 mm Effect of Resolution on Rat Brain phantom 2 mm 1 mm 0.5 mm 0.25 mm 0 mm

27. State-of-the-art pinhole SPECT A-SPECT: two pinholes. Mouse rotates in tube Mouse rotates in tube Thyroid of mouse (I-125) (I-125) Mouse bone scan (Tc-99m)

28. Micro-SPECT

29. Simulations: A-SPECT vs. Micro-SPECT Truth Micro-SPECT A-SPECT

30. Finally: We need a ready set of detectors plus associated electronics Solid state? SPECIFICATIONS Energies of 30-140keV Counting mode –Capture efficiency >80% @140keV –Spatial resolution: 200 microns –Energy resolution (10-20%) Contact Freek beekman: f.beekman@azu.nl +31 30 250 7779 We need approx. 40 detector elements. ~10 mm ~30 mm