Magnetic resonance imaging in biomedical research Igor Sera

Magnetic resonance imaging in biomedical research Igor Serša Ljubljana, 2011

History of Nuclear Magnetic Resonance (NMR) Purcell, Torrey, Pound (1946) Bloch, Hansen, Packard (1946) 1 D 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 B 0 = 1, 5 T, opening 60 cm High-reolution NMR/MRI system Use in chemistry, MR microscopy B 0 = 7 T, opening 3 cm

Nuclear magnetization

Nuclear precession Mz B 0 M 0/2 RF pulse B 1 field 100 MHz proton precession frequency in 2. 35 T T 1 ln(2) t

MR signal FID signal Ui U 0 t M FT w Ui w spectrum

Magnetic field gradients B 0 Gx x x + x = B Sedle coil Maxwell pair x

MR imaging in one dimension B x w 0 w B x w

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 m. T/m • Gradient rise time of 200 T/m/ms • 600 A @ 2000 V = 1. 2 MW ! RF amplifiers • 35 k. W 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 with magnetization preparation Steady state GE Contrast enhanced steady state GE Balanced steady state GE Echoplanar Hybrid echo Principles Advantages Disadvantages simple, SE T 1, T 2, DP contrast SE several TE, several images Contrast Slow (especially in T 2) DP + T 2 images Slow, even if acquisition of the 2 nd 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 T 1 weighting Tissue suppression signal if TI is adapted to T 1 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 < T 2 Gradients / RF dephasers + speed T 2* not T 2 T 1, DP weighting small α and very short TR Gradients / RF dephasers k-space optimization ++ speed cardiac perfusion Poor T 1 weighting + preparation pulse: - IR (T 1 weighted) - T 2 sensibilization TR < T 2 Rephasing gradients FID Rephasing gradients Hahn echo ( true. T 2) Balanced gradients in all 3 directions T 2/T 1 contrast ++ speed Angio. MRI Gado Cardiac perfusion / viability + signal ++ speed Not much signal T 2 weighted ++ signal, ++ speed Flow correction Single GE or multi shot Preparation by SE (T 2), GE (T 2*), IR (T 1), DW Exacting for gradients ++++ speed Perfusion MRIf BOLD Diffusion Limited resolution Artifacts Fast SE + intermediary GE ++ speed SAR reduction Low signal to noise ratio Complex contrast

Clinical MR images f. MRI Fiber tracking MRI of spine MR angiography DWI - stroke MRI – brain tumors

New reconstruction methods 0 Sa’ R = 4 Sb’ Sc’ Sd’ 0 0 = 0 0 0 0 0 0 0 S

Small animal MRI Experimental mice Anaesthesia Placement in the probe Resolution × SNR const($$$) 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 • CD 8 cell mediated disease 7 days post infection Cho Cr NAA Before infection Normal cord MS cord T 2 -weighted images MS lesions (demyelinated choppy structures) appear bright Decrease in NAA/Cr ratio in early stage of MS.

Superparamagnetic labells • • • Superparamagnetic antibodies under scanning electron microscope attached to CD 8 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 CD 8 labeling B 6 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 2 D 10 fold resolution increase 3 D 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 7 – 14 T

How to achieve high resolution? By the use of stronger gradients GR Δt 45 m. T/m @ 750 A Conventional MRI GR 1500 m. T/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 m. T/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 30 mm • ηk = 1. 8·ηH 20 = 0. 0018 Pas • ρk = 1035 kg/m 3 0, 5 l plazma + rt-PA 3 mm pump Dp = 15 k. Pa (113 mm. Hg), arterial system Dp = 3 k. Pa (22 mm. Hg), 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 2 D MR microscopy using spin-echo MRI sequence Fast flow 0 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 flow Počasen tok x 1 0. 4 0. 2 T S 0 0 0 500 1000 1500 2000 2500 t [s] S 0 S t 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 • 3 D RARE MRI (fast flow, ∆p = 15 k. Pa) 0 min 36 min

NMR in studies of thrombolysis • Blood clot dissolution progresses radially with regard to the perfusion channel along the clot. 2 R∞ • • 2 R 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

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 2 R Layer of the clot that is removed in time dt • d. R Start of thrombolytic biochemical reactions is delayed (τ) and gradual (Δ) 1/c∞ τ Δ t

NMR in studies of thrombolysis Perfussion channel profile Thrombolytic time 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 2. Ampere law Thin-sample approximation Current encoding part Imaging part

Current density imaging Electrode setup experiment Phase image simulation 2 D current density field

MRI of wood On a 3 m high beech tree, transplanted in a portable pot, a branch of 5 mm 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 Molars bifurcation 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 2 D 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.