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The TRIMAGE project: A Trimodality PET/MR/EEG Brain Scanner for Early Diagnosis of Schizophrenia and Other Mental Disord

The TRIMAGE project aims to find new biomarkers and develop a cost-effective trimodality imaging instrument for the early diagnosis, monitoring, and follow-up of schizophrenia and other mental disorders using PET, MR, and EEG technologies.

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The TRIMAGE project: A Trimodality PET/MR/EEG Brain Scanner for Early Diagnosis of Schizophrenia and Other Mental Disord

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  1. “The TRIMAGE project: A Trimodality (PET/MR/EEG) brain scanner for early diagnosis of schizophrenia and other mental disorders” Alberto Del Guerra(Trimage Coordinator) Department of Physics, University of Pisa, Italy <alberto.del.guerra@unipi.it>

  2. CONTENTS • The TRIMAGE project • Biomarkers and • Multimodal Paradigm • The PET/MR/EEG • symultanoeus scanner

  3. The TRIMAGE project

  4. Eleven Partners • Physics and technology (5): • UNIVERSITA’ DI PISA (the Coordinator) (UNIPI) • TECHNOLOGICAL EDUCATIONAL INSTITUTION OF ATHENS (TEIA) • FORSCHUNGSZENTRUM JUELICH GMBH (JÜLICH) • KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN (TUM) • ISTITUTO NAZIONALE DI FISICA NUCLEARE TORINO ( INFN) • Clinical experience in neurology/psychiatry (2): • UNIVERSITAET KLINIKUM AACHEN (AACHEN) • UNIVERSITAET ZUERICH ( UZH) • High tech SMEs (4): • ADVANSID SRL (Advansid) • WEEROC SAS ( Weeroc) • RAYTEST ISOTOPENMESSGERAETEGmbH (raytest) (TERMINATED 31 May 2015) • RS2D (RS2D) • ------------------------------------------------------------------------------------------------------------------------ • 11 Partners from Europe: • 3 Italy (Coord +2), (3+1) Germany, 2 France, 1 Greece,1 Switzerland • ------------------------------------------------------------------------------------------------------- • Starting day: 1 December 2013- Duration: 4 years

  5. The OBJECTIVES S&T objective 1: Find new biomarkers and define a suitable multimodal paradigm with already available PET, MR, EEG and PET/MR systems that provides clinical evidence on the feasibility of schizophrenia early diagnosis. S&T objective 2: Construct and test an optimized cost-effective trimodality imaging instrument (brain PET/MR/EEG) for diagnosis, monitoring and follow-up of schizophrenia disorders. S&T objective 3: Validate the trimodal imaging device built by this Consortium based on the results and the clinical data obtained from objective 1.

  6. Biomarkers and Multimodal Paradigm

  7. Biomarkers and Multimodal Paradigm • Loudness Dependence of Auditory Evoked Potential (LDAEP) as a biomarker, based on the Serotonin Hypothesis. i.e. reduced LDAEP in patientshigher serotonergic activities. • Not to focus on one biomarker, but on multiple levels of analysis and abstraction by simultaneously using information from PET/MR/EEG data • Integrate these information in machine learning algorithms to improve specificity and sensitivity

  8. Schizophrenia Clinical phenotype Dimensionalsymptoms Pathophysiologicalmechanism Neuroimaging phenotype Biological pathway Genes s Positive symptoms Formal thought disorders Negative symptoms Personality Impulsivity Response inhibition Change detection ... ... MMN LDAEP Candidate biomarkers glutamate serotonin dopamine GABA 5-HT1B SERT COMT adapted from Hasler & Northoff, 2011

  9. Biomarkers and Multimodal Paradigm • Validation of LDAEP with multimodal approach: • fMRI - To obtain spatial correlation with EEG • PET - To study influences of other neurotransmitters, e.g. • [18F]-fluorodopa for kinetic analysis in the striatum (TUM) • [11-C]flumazenil ,targeting the GABA-ergic system and resting state networks via fMRI in a rest-task-rest design (Aachen-Julich)

  10. Patients recruiting • First phase (utilizing the available EEG, PET, MR and PET/MR devices available to the collaboration in Munich and Joulich): • 40 patients with schizophrenia diagnosis according to ICD-10 • (20 @TUM; 20@Julich) • - 40 age and gender matched healthy control • (20 @TUM; 20@Julich) • The first phase will produce •  Biomarkers and Multimodal Paradigm • Second and Final phase(for the assessment of the EEG/PET/MR protoytpe):- 20 schizophrenic patients • 20 prodromal individuals • 20 healthy controls matched in age, gender, education, IQ, etc..

  11. Kinetic analysis 18F-FDOPA in schizophrenia @TUM Acquisition protocol: Sequence length not shown to scale Dixon UTE rsfMRI GRE hrfMRI striatum T1w T2tse T2flash T2flair ASL DTI hrfMRI hippocamp PET 10 schizophrenic patients and 3 controls scanned in the Siemens Biograph mMR (Nuclear medicine, Klinikum rechts der Isar, Munich). PET data acquired in list-mode format for 70 minutes. 3D affine registration of every frame to the static reconstruction. Extract cerebellum and striatum using the Harvard-Oxford template with Statistic Parametric Map-8. Patlak analysis in the striatum using the cerebellum as reference tissue to estimate the maro-parameter Ki: Net influx rate of DOPA in the striatum.

  12. Kinetic analysis 18F-FDOPA in schizophrenia @TUM Ki value measured from 15—70 minutes after injection in the striatum Loco regional (executive, limbic and sensorimotor) differences [limbic the highest] VERY PRELIMINARY Exemplar time activity curve Static reconstruction Dynamic reconstruction Voxel-wise analysis

  13. LOCO-regional analysis limbic sensorimotor executive

  14. The PET/MR/EEG system

  15. The PET/MR/EEG System The hardware system will be engineered with the intent of making the instrument a cost-effective and "beyond the state of the art“ product, for the simultaneous PET_MR _EEG imaging of a patient. The instrument will comprise a 1.5 T cryogen free, very compact superconducting magnet, a PET insert based on silicon photomultiplier with better performances (2 mm FWHM spatial resolution, ~14% sensitivity) than any available clinical PET scanner and a fully integrated EEG.

  16. A closer LOOK at the PET/MR/EEG instrument Artistic view of the dedicated brain PET/MR/EEG system. The EEG cap is not shown.

  17. The MR System Technical room: Cryocooler Gradient amplifiers RF amplifier Power supplies Monitoring unit Magnet B0 at 1.5 T Gradient coil RF coil

  18. The MR System • Field homogeneity +/- 1 ppm • over 15 cm Diameter Sphere • Active shielding: 5 Gauss lIne • fringe field from center • Axial < 2.8 m • Radial < 2.2 m • Gradient • - External diameter 712 mm • - Internal diameter 580mm • Gradient coil: • - Maximum strength – 42mT/m (X,Y), • 41.2 mT/m (Z) • - Slew rate – 123T/m/s (X,Y),127T/m/s (Z) • RF coil Tx/Rx 8 channels • quadrature birdcage with • distributed capacitors. • - Outer diameter = 310 mm • - Inner diameter = 260 mm •  Head diameter • MR sequences: • UTE – Attenuation correction • MPRAGE – Anatomical information • FLAIR – Anatomical information • EPIK2 – High resolution functional information

  19. The PET System Detector (18 in total) Approximately 54 mm x 162 mm The PET component is designed to provide performance beyond the state of the art for clinical PET systems with an expected spatial resolution of about 2 mm FWHM. The PET field-of-view will be 162 mm axially and 240 mm diameter with an open bore of 308 mm diameter. The PET detector comprises 216 tiles featuring two layers of LYSO crystal matrices (3.4 mm pitch) with half pitch staggering. Module (3 per detector) Tile (4 per module) Full-ring PET A single sector of the PET system

  20. The PET System Each tile comprises two layers of LYSO crystal matrices (3.4 mm pitch) with half pitch staggering Top: 7 x 7 crystals of 3.3 x 3.3 x 8 mm3 Bottom: 8 x 8 crystals of 3.3 x 3.3 x 12 mm3 Crystals in bottom layer are one to one coupled to SiPMs The SiPM module comprises eight matrices of 8 x 4 NUV SiPMs manufactured by AdvanSID. Picture of the detector module made up of four tiles.

  21. Photons interacting in different layers are expected to produce different light patterns on the SiPMs Interaction in the bottom layer One single SiPM activated Crystal identification is based on a support vector machine: 93% accuracy. Interaction in the top layer Four clustered SiPM activated

  22. Preliminary evaluation of the energy resolution of LYSO crystals

  23. PET Image reconstruction w/ PRESTO Toolkit* *Scheins J et al. IEEE Trans Med Imag. 2011. 30(3): 879-892. System matrix: Analytical calculation of volumes of intersection between crystal pairs and image elements. Exploit cylindrical symmetries to reduce the system matrix file size and reconstruction time Dual crystal layer and crystal attentuation are included in the model Parallel implementation of ML-EM Exploits cylindrical symmetries to reduce the system matrix

  24. Reconstructed PET simulated data Brain phantom with [18F]-FDG simulated for 10 minutes reconstructed after 100 iterations. NEMA phantom simulated for 60 minutes reconstructed after 100 iterations (smallest diameter rod 10mm)

  25. Scatter in the object Energy spectrum for events with different types of interactions Phantom filled with water. 2,000 s simulation time. 20 cm active rod (1 MBq=37mCi) • Scatter fraction evaluation (350-650 keV): • Non-scattered photons – 63.4% • SF (single scatter) – 30.4% • SF (multiple scatter) – 6.2% Monte Carlo simulations (GATE) used to estimate the scatter fraction.

  26. Attenuation Correction on patient µ-map of exemplar patient Regional 18F-FDG uptake error CT Dixon UTE R2-dUTE Siemens Biograph mMR Processed R2-map based on a dual Ultrashort TE sequence1. 1Cabello J et al. J Nucl Med. 2015. 56(3): 426-429.

  27. The PET System Expected Performance • High Spatial resolution 2 mm (DOI) • High Efficiency (7% at CFOV) • Axial FOV = 150mm • Transaxial FOV =120 mm radius

  28. MRI magnet PET-MR InterferenceThe PET System: between the Gradient coil and the RF coil 360 mm Gradient coil + Shimmers 290 mm PET Space 155 mm MRI head coil 130 mm Empty space 120 mm PET FOV center 28

  29. The DAQ system INSIDE the MR OUTSIDE the MR TX TX TX TX TX TX MB RX RX RX Host PC LVDS + slow control Coinc. PU RX FPGA Triroc ASIC TX FPGA 9X MB FPGA USB 2.0 Each tile is read out by a 64-channel Triroc ASICs and transmitted to the TX-FPGA. The ASIC transmits, for each event, the timestamp and charge of each SiPM output pulse. The back-end is composed by a motherboard (MB) and 9 RX boards. The RX board acts as a multiplexing interface while the MB sorts events and transmits coincidences only to the host PC via USB 2.0 link.

  30. The PET cassette Shielded cassette LYSO CRYSTALS

  31. Time schedule of TRIMAGE project(with reference to the S&T objectives) Biomarkers and Multimodal Imaging Paradigm  completed by December 2016 The PET/MR/EEG Prototype  completed,tested and installed in JULICH by June 2017 Clinical Validation of the new PET/MR/EEG Prototype  completed by December 2017 Very challenging!

  32. The TRIMAGE Collaboration • PISA: • Belcari, N • Biagi, L • Bisogni, MG • Camarlinghi, N • Del Guerra, A (PI) • Morrocchi, M • Sportelli, G • Tosetti, M • Zaccaro, E • INFN: • Cerello, P • Coli, S • Giraudo, G • Pennazio, F • Trinchero, R • JULICH: • Berneking, A • Choi, CH • Lerche, C • Rota-Kops, E • Scheins, J • Shah, J • AACHEN: • Neuner, I • TUM: • Avram, M • Cabello, J • Sorg, C • Ziegler, S • ZURICH: • Heekeren, K • Kawohl, W • ATHENS: • Georgiou, M • Loudos, G • Papadimitroulas, P • ADVANSID: • Colpo, S • Piemonte, C • Serra, N • WEEROC: • Ahmad, S • De la Taille, C • Fleury, J • RS2D: • Bedet, J • Lefaucheur, JL • Muller, J • Schimpf, R

  33. The TRIMAGE Collaboration

  34. Thank you for your attention!

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