Magnetic resonance imaging in biomedical research Igor Serša Ljubljana, 2011 History of Nuclear Magnetic Resonance (NMR) Purcell, Torrey, Pound (1946) Bloch, Hansen, Packard (1946) 1D NMR spectroscopy (CW) Pulsed NMR Emergence of computers P.C. Lauterbur (1973) P. Mansfield (1973) R.R. Ernst (1975) Multidimensional NMR spectroscopy NQR , Solid state NMR, NMR in Eart‘s field Biomedcial use of NMR, magnetic resonance imaging (MRI) Nobel Laureates in MRI R.R. Ernst 1991 chemistry For a discovery of multidimensional NMR and setting foundations of Fourier transform MRI methods P. Mansfield 2003 medicine For the development of fast MRI (Echo planar imaging) P.C. Lauterbur 2003 medicine First who succeded to get a MR image MRI in early days Lauterbur, P.C. (1973). Nature 242, 190. … and MRI now MRI statistics • MRI Equipment Market of 5.5 Billion Dollars in 2010 • 91.2 MRI exams are performed per 1,000 population per year in USA • 41.3 MRI exams are performed per 1,000 population per year in OECD countries • 22.2 MRI exams are performed per 1,000 population per year in Slovenia • 7,950 MRI scanners in USA (25.9 MRI scanners per million population) • 18 MRI scanners in Slovenia (9 MRI scanners per million population) Opening ceremony of the last MRI scanner in Slovenia (Murska Sobota) Investment of 1,200,000 € MRI systems Clinical MRI system Use in radiology B0 = 1,5 T, opening 60 cm High-reolution NMR/MRI system Use in chemistry, MR microscopy B0 = 7 T, opening 3 cm Nuclear magnetization M p mi i V Nuclear precession Mz B0 M0 M0/2 RF pulse B1 field T1 ln(2) B1 t p 0 B0 100 MHz proton precession frequency in 2.35 T t MR signal FID signal Ui U0 t M FT Ui spectrum Magnetic field gradients B0 x Gx x + x = B Sedle coil Maxwell pair x MR imaging in one dimension B x 0 ( x ) 0 B x ( x ) 0 G x x MR imaging in two dimensions back projection reconstruction method Pulse sequences RF p p/2 AQ Gx Gy Gz TE MRI in biomedicine Research on clinical MR scanners Hardware development • RF coils • Gradient coils • Amplifiers • Spectrometers Imaging sequences • Standard MRI • Contrast • Speed • Resolution • Spectroscopic Data processing • New reconstruction algorithms • Image filtering • Mathematical modelling Rsearch on other MRI systems MR microscopy • MRI of wood • Pharmaceutical studies • Porous materials • Biologoical Tissue properties • MRI of food Small anaimal MRI • Development of new MRI contrast agents • Study of new drugs Hardware development Multi channel RF coils (32 channel head coil) Gradient amplifiers • Gradients up to 45 mT/m • Gradient rise time of 200 T/m/ms • 600 A @ 2000 V = 1.2 MW ! RF amplifiers • 35 kW MRI magnets • 1.5 T, 3 T, 7 T • Low weight • Compact dimensions • Low helium consumption Imaging sequences Type of sequence Spin echo (SE) Multiecho SE Fast SE Ultrafast SE IR STIR FLAIR Gradient echo (GE) GE with spoiled residual transverse magnetization Ultrafast GE Ultrafast GE with magnetization preparation Steady state GE Contrast enhanced steady state GE Balanced steady state GE Echoplanar Hybrid echo Principles Advantages Disadvantages simple, SE T1, T2, DP contrast SE several TE, several images Contrast Slow (especially in T2) DP + T2 images Slow, even if acquisition of the 2nd image does not lengthen acquisition SE, echo train effctive TE SE, long echo train, half-Fourier Faster than simple SE simple ES contrast Even faster Fat shown as a hypersignal RF 180°, TI + ES/ESR/EG T1 weighting Tissue suppression signal if TI is adapted to T1 Longer TR / acquisition time IR, short TI 150 ms Fat signal suppression Longer TR / acquisition time IR, long TI 2200 ms CSF signal suppression Longer TR / acquisition time < 90° α and short TR No rephasing pulse TR < T2 Gradients / RF dephasers + speed T2* not T2 small α and very short TR Gradients / RF dephasers k-space optimization ++ speed cardiac perfusion + preparation pulse: - IR (T1weighted) - T2 sensibilization TR < T2 Rephasing gradients FID Rephasing gradients Hahn echo ( trueT2) Balanced gradients in all 3 directions T2/T1contrast ++ speed AngioMRI Gado Cardiac perfusion / viability + signal ++ speed Single GE or multi shot Preparation by SE (T2), GE (T2*), IR (T1), DW Exacting for gradients ++++ speed Perfusion MRIf BOLD Diffusion Fast SE + intermediary GE ++ speed SAR reduction Low signal to noise ratio T1, DP weighting Poor T1 weighting Complex contrast Not much signal T2 weighted ++ signal, ++ speed Flow correction Limited resolution Artifacts Clinical MR images fMRI Fiber tracking MRI of spine MR angiography DWI - stroke MRI – brain tumors New reconstruction methods 0 Sa’ 0 = Sc’ Sd’ 0 0 Sb’ R=4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 S Small animal MRI Experimental mice Anaesthesia Placement in the probe Resolution Resolution × SNR const($$$) Time Time Signal Noise Multiple sclerosis model • Mice having Theiler’s Murine Encephalitis Virus infection (TMEV) may develop symptoms similar to that of multiple sclerosis • Intracerebral injection causes demyelinating disease • CD8 cell mediated disease 7 days post infection Cr Cho NAA Before infection Normal cord MS cord 6 T2-weighted images MS lesions (demyelinated choppy structures) appear bright 5 4 3 2 1 ppm 0 Decrease in NAA/Cr ratio in early stage of MS. Superparamagnetic labells • • • • • Superparamagnetic antibodies under scanning electron microscope attached to CD8 cells. USPIO - Ultrasmall Super Paramagnetic Iron Oxide particle: 50 nm in diameter Highly specific superparamagnetically labeled antibodies: targeted USPIO-s Venous administration Signal persists for days, excellent specificity A single labeled cell can theoretically provide adequate signal to be visualized MS lesions detected by CD8 labeling B6 strain mice (acute demyelinating disease, full recovery in 4-6 weeks) Day 0 Day 3 Day 7 Day 21 Day 45 What is MR Microscopy? MR microscopy is essentially identical to conventional MRI (most of MR sequences of clinical MRI can be used) except that resolution is at least an order of magnitude higher. Signal -> Signal / 100 Conventional MRI 1 mm / pixel 2D 10 fold resolution increase 3D 10-100 µm / pixel MR microscopy Signal -> Signal / 1000 How to compensate the signal loss? • • • • By using stronger magnets By lowering the sample temperature (not an option) By signal averaging By reducing RF coil size RF coils in sizes from 2 mm – 25 mm Signal B 0 7 – 14 T 2 How to achieve high resolution? By the use of stronger gradients GR Δt 45 mT/m @ 750 A Conventional MRI FOV 2p GR t GR 1500 mT/m @ 60 A MR microscopy Δt MRI laboratory at JSI 100 MHz (proton frequency) 2.35 T Horizontal bore superconducting magnet Accessories for MR microscopy Top gradients of 250 mT/m, RF probes 2-25 mm Our research using MR microscopy Electric current density imaging NMR of porous materials MRI of wood NMR in studies of thrombolysis Volume selective excitation MRI in pharmaceutical research http://titan.ijs.si/MRI/index.html MRI in dental research NMR in studies of thrombolysis blood clot magnet 0,7 mm 3 mm 30 mm • ηk = 1.8·ηH20 = 0.0018 Pas • ρk = 1035 kg/m3 0,5 l plazma + rt-PA 3 mm pump p = 15 kPa (113 mmHg), arterial system p = 3 kPa (22 mmHg), venous system Flow regime v [m/s] Re Fast flow begining 4,26 1660 end 0,86 1430 Slow flow begining 0,19 75 end 0,01 18 NMR in studies of thrombolysis TE = 12 ms TR = 400 ms SLTH = 2 mm FOV = 20 mm Matrix: 256 x 256 Dynamical 2D MR microscopy using spin-echo MRI sequence Fast flow 0 min 4 min 8 min 12 min 16 min 4 min 8 min 12 min 16 min Slow flow 0 min NMR in studies of thrombolysis 1 x 0.8 Hiter tok Fast flow 0.6 Slow flowtok Počasen x 1 x 1 S / S 0.4 0.2 T S0 0 0 500 1000 1500 2000 2500 t [s] S0 t S S∞ SERŠA, Igor, TRATAR, Gregor, MIKAC, Urška, BLINC, Aleš. A mathematical model for the dissolution of non-occlusive blood clots in fast tangential blood flow. Biorheology (Oxf.), 2007, vol. 44, p. 1-16. NMR in studies of thrombolysis • 3D RARE MRI (fast flow, ∆p = 15 kPa) 0 min 36 min 1,2 1,0 t = 0 min 0,8 0,6 0,4 0,2 0,0 0 2 4 6 8 10 12 entrance length z [mm] channel radius R [mm] channel radius R [mm] 1,2 t = 36 min 1,0 0,8 0,6 0,4 0,2 0,0 0 2 4 6 8 10 12 entrance length z [mm] NMR in studies of thrombolysis • Blood clot dissolution progresses radially with regard to the perfusion channel along the clot. 2R∞ • • 2R v 0 V / (p R ) 2 Volume blood flow through the clot is constant. Mechanical forces to the surface of the clot have viscous origin and are therefore proportional to the shear velocity of blood flow along the clot. Confocal microscopy of thrombolysis F λ 5 μm J. W. Weisel, Structure of fibrin: impact on clot stability, J Thromb Haemost 2007 v v v dA F ds S dt S r r r 2 ( z ) dt rR NMR in studies of thrombolysis • Mechanical work needed for the removal of the clot segment is proportional to its volume. λ Layer of the clot that is well perfused with the thrombolytic agent dA c dV c S dR 2R Layer of the clot that is removed in time dt • dR Start of thrombolytic biochemical reactions is delayed (τ) and gradual (Δ) 1/c 1/c∞ 1 c (t ) 1 1 c 1 exp(( t ) / ) τ Δ t NMR in studies of thrombolysis Perfussion channel profile R R ( z, t tD ) 1 R 1 exp(( t ) / ) 0 ln T7 R 1 exp( / ) 7 1 1 z z0 4 2 7 ; z z0 ; z z0 1 7 R 1 exp(( t ) / ) 0 R ln T7 R 1 exp( / ) 7 z z0 ; . Thrombolytic time 7 T R0 7 ln exp 1 1 R tD ( z ) T R ln exp 7 1 0 R 1 7 z z0 4 2 1 exp 1 1 exp 1 ; z z0 . SERŠA, Igor, VIDMAR, Jernej, GROBELNIK, Barbara, MIKAC, Urška, TRATAR, Gregor, BLINC, Aleš. Modelling the effect of laminar axially directed blood flow on the dissolution of non-occlusive blood clots. Phys. Med. Biol., 2007, vol. 52, p. 2969-2985. NMR in studies of thrombolysis Current density imaging Externally applied electric field is used to induce cell permeability by transient or permanent structural changes in membrane The aim of this study was to monitor current density during high-voltage electroporation (important for electrode design and positioning) Current density imaging Electroporation phantom Current density imaging Effect of electric pulses Current density imaging Electric pulses CDI calculation • Two 20 ms pulses @ 15 V • Eight 100 μs pulses @ 1000 V 1. Phase is proportional to Bz CDI x, y Bz x, y t 2. Ampere law 1 B z B y j CDI , 0 y z B x z B z x , B y x Thin-sample approximation 1 B z j CDI , 0 y Current encoding part Imaging part B z x , 0 B x y Current density imaging Vector field (jx,jy) 30 16 14 25 12 20 y 10 8 15 6 10 4 2 5 2 5 10 Vector field (jx,jy) 15 20 25 4 6 8 10 12 14 30 x 30 16 14 25 12 20 10 y 8 15 6 4 10 2 5 Electrode setup 16 30 25 experiment 20 15 10 5 14 12 10 6 4 simulation x Phase image 8 2D current density field 2 16 MRI of wood On a 3m high beech tree, transplanted in a portable pot, a branch of 5mm diameter was topped. The topped branch was then inserted in the RF coil and then in the magnet. MRI of wood Pith, xylem rays, early wood vessels and cambial zone 6 mm 21 mm MRI of wood • Trees do not have a mechanism to heal wounds like higher organisms (animals, humans), i.e., wounds are not gradually replaced by the original tissue. • In trees wounds are simply overgrown by the new tissue, while the wounded tissue slowly degrades. Wound Dehydration and dieback new grown tissues Formation of the reaction zone MRI of wood Day 1 Day 3 Day 8 MRI of wood Day 14 Day 28 Day 168 MRI in dental research enamel Premolars 1-2 root channels periodontal communications dentin pulp bifurcation Molars 3-4 root channels (in the literature was reported even up to 7 root channels) root channel MRI in dental research Root channels are not clearly visible. Root channels after endodontic treatment. • Standard X-ray image corresponds to 2D projection of hard dental tissues (enamel and dentin) into a plane of image. • It is impossible to accurately determine the exact number of root channels since they may overlap in the projection. • Fine details (periodontal communications and anastomosis) cannot be seen due to limited resolution. • X-ray scanning is harmful due to X-ray radiation. MRI in dental research X-ray image Hard dental tissues are bright on the images, soft tissues cannot be seen. MR image obtained after co-addition of all slices Soft dental tissues are bright on the images, hard tissues cannot be seen. Frontal (bucco-lingual) as well as side (mesio-distal) view is possible. MRI in dental research MRI in dental research Conclusion • MRI is very versatile. • Its applications range from clinical routine in radiology to research in medicine, biology as well as in material science. • Close collaboration between scientists and industrial engineers enabled an enormous development of MRI from an unreliable imaging modality to the new radiological standard.