magnetic resonance imaging in biomedical research igor serša ljubljana, 2011

Magnetic resonance imaging in biomedical research

Igor Serša

Ljubljana, 2011

History of Nuclear Magnetic Resonance (NMR)

MultidimensionalNMR spectroscopy

Biomedcial use of NMR, magnetic resonance imaging (MRI)

1D NMR spectroscopy (CW)

NQR ,Solid state NMR,NMR in Eart‘s field

Emergence of computersPulsed NMR

R.R. Ernst (1975)

P.C. Lauterbur (1973)P. Mansfield (1973)

Purcell, Torrey, Pound (1946)Bloch, Hansen, Packard (1946)

Nobel Laureates in MRIR.R. Ernst 1991 chemistry

P. Mansfield 2003 medicine

P.C. Lauterbur 2003 medicine

For a discovery of multidimensional NMR and setting foundations of Fourier transform MRI methods

For the development of fast MRI (Echo planar imaging)

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 systemUse in radiologyB0 = 1,5 T, opening 60 cm

High-reolution NMR/MRI system Use in chemistry, MR microscopyB0 = 7 T, opening 3 cm

Nuclear magnetization

m ii

pM

V

Nuclear precession

B0

RF pulseB1 field

100 MHz proton precession frequency in 2.35 T0 0B

1 pB t

M0/2

M0

tT1 ln(2)

Mz

MR signal

Ui

M

w

Ui

t

U0

FT

w

FID signal

spectrum

Magnetic field gradients

x

x

B0

B

x

Gx x+

=

Sedle coil Maxwell pair

MR imaging in one dimension

x xB B

w0 w w

0( )x 0( ) xx G x

MR imaging in two dimensions

back projection reconstruction method

Pulse sequences

RF

AQ

Gx

Gy

/2pp

TE

Gz

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 developmentMulti 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 sequencesType of sequence Principles Advantages Disadvantages Spin echo (SE) simple, SE

T1, T2, DP contrast Contrast Slow (especially in T2)

Multiecho SE SE several TE, several images DP + T2 images Slow, even if acquisition of the 2nd image does not lengthen acquisition

Fast SE SE, echo train effctive TE

Faster than simple SE simpleES contrast

Fat shown as a hypersignal

Ultrafast SE SE, long echo train, half-Fourier Even faster Low signal to noise ratio

IR RF 180°, TI + ES/ESR/EG T1 weighting Tissue suppression signal if TI is adapted to T1

Longer TR / acquisition time

STIR IR, short TI 150 ms Fat signal suppression Longer TR / acquisition time

FLAIR IR, long TI 2200 ms CSF signal suppression Longer TR / acquisition time

Gradient echo (GE) < 90° α and short TR No rephasing pulse

+ speed T2* not T2

GE with spoiled residual transverse magnetization

TR < T2 Gradients / RF dephasers

T1, DP weighting

Ultrafast GE small α and very short TR Gradients / RF dephasersk-space optimization

++ speedcardiac perfusion

Poor T1 weighting

Ultrafast GE with magnetization preparation

+ preparation pulse:- IR (T1weighted)- T2 sensibilization

++ speedAngioMRI GadoCardiac perfusion / viability

Steady state GE TR < T2 Rephasing gradients FID

+ signal++ speed

Complex contrast

Contrast enhanced steady state GE Rephasing gradientsHahn echo ( trueT2)

Not much signalT2 weighted

Balancedsteady state GE

Balanced gradients in all 3 directionsT2/T1contrast

++ signal, ++ speedFlow correction

Echoplanar Single GE or multi shotPreparation by SE (T2), GE (T2*), IR (T1), DWExacting for gradients

++++ speedPerfusionMRIf BOLDDiffusion

Limited resolution Artifacts

Hybrid echo Fast SE+ intermediary GE

++ speedSAR reduction

Clinical MR images

fMRI Fiber tracking MRI of spine

MR angiography DWI - stroke MRI – brain tumors

New reconstruction methods

R = 4

Sa’

Sb’= S

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

0 0 0 0

Sc’

Sd’

Small animal MRI

Experimental mice Anaesthesia Placement in the probe

const($$$)Resolution × SNRTime

SignalNoise

Resolution

Time

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

Normal cord MS cord

T2-weighted imagesMS lesions (demyelinated choppy structures) appear bright

6 5 4 3 2 1 0ppm

7 days post infection

Before infection

NAA

CrCho

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

Day 0

Day 3

Day 7

Day 21

Day 45

B6 strain mice (acute demyelinating disease, full recovery in 4-6 weeks)

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.

1 mm / pixel

10-100 µm / pixel

Conventional MRI

MR microscopy

2D

3D

10 fold resolution increase

Signal -> Signal / 100

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

7 – 14 T

20Signal B

RF coils in sizes from 2 mm – 25 mm

How to achieve high resolution?By the use of stronger gradients

45 mT/m @ 750 A

1500 mT/m @ 60 A

Conventional MRI

MR microscopy

Δt

GR

Δt

GR

2

R

FOVG t

MRI laboratory at JSI100 MHz (proton frequency)2.35 THorizontal bore superconducting magnet

Accessories for MR microscopyTop gradients of 250 mT/m, RF probes 2-25 mm

Our research using MR microscopy

http://titan.ijs.si/MRI/index.html

Electric current density imaging NMR of porous materials MRI of wood

Volume selective excitation MRI in pharmaceutical research

NMR in studies of thrombolysis

MRI in dental research

NMR in studies of thrombolysis

pump

magnet

3 mm0,7 mm

30 mm

Dp = 15 kPa (113 mmHg), arterial system

Dp = 3 kPa (22 mmHg), venous system

blood clot

0,5 l plazma + rt-PA

3 mm

Flow regime v [m/s] Re

Fast flow

begining 4,26 1660

end 0,86 1430

Slowflow

begining 0,19 75

end 0,01 18

• ηk = 1.8·ηH20 = 0.0018 Pas• ρk = 1035 kg/m3

NMR in studies of thrombolysisTE = 12 msTR = 400 msSLTH = 2 mmFOV = 20 mmMatrix: 256 x 256

0 min 4 min 8 min 12 min 16 min

0 min 4 min 8 min 12 min 16 min

Slow flow

Fast flow

Dynamical 2D MR microscopy using spin-echo MRI sequence

NMR in studies of thrombolysis

1 /x S S

S∞

SS0S0

x1

t

T

0 500 1000 1500 2000 25000

0.2

0.4

0.6

0.8

1

Hiter tok

Počasen tok

t [s]

x

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.

Fast flow

Slow flow

NMR in studies of thrombolysis

• 3D RARE MRI (fast flow, ∆p = 15 kPa)

0 min 36 min

0 2 4 6 8 10 120,0

0,2

0,4

0,6

0,8

1,0

1,2

t = 36 min

channel r

adiu

s R

[m

m]

entrance length z [mm]0 2 4 6 8 10 12

0,0

0,2

0,4

0,6

0,8

1,0

1,2

channel r

adiu

s R

[m

m]

entrance length z [mm]

t = 0 min

NMR in studies of thrombolysis

2

( )r R

v v vdA Fds S dt S z dt

r r r

• Blood clot dissolution progresses radially with regard to the perfusion channel along the clot.

• 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.

20 / ( )Vv R2R∞ 2R

λ

FConfocal microscopy of thrombolysis

5 μm

J. W. Weisel, Structure of fibrin: impact on clot stability, J Thromb Haemost 2007

• Mechanical work needed for the removal of the clot segment is proportional to its volume.

• Start of thrombolytic biochemical reactions is delayed (τ) and gradual (Δ)

NMR in studies of thrombolysis

dA c dV c S dR

1 1 1

( ) 1 exp(( ) / )c t c t

τ

Δ

t

1/c∞

1/c

2R

dR

Layer of the clot that is well perfused with the thrombolytic agent

Layer of the clot that is removed in time dt

λ

NMR in studies of thrombolysis

1

7 7240

0 07

17 7

00

7

1 exp(( ) / )ln 1 1 ;

1 exp( / )( , )

1 exp(( ) / )ln ; .

1 exp( / )

D

R tR z z z z

TRR z t t

R tR z z

R T

7 24

7 00 0

7

7 00

ln exp 1 1 1 1 exp 1 ;

( )

ln exp 1 1 exp 1 ; .

D

T Rz z z z

Rt z

T Rz z

R

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

The aim of this study was to monitor current density during high-voltage

electroporation (important for electrode design and positioning)

Externally applied electric field is used to induce cell permeability by transient or

permanent structural changes in membrane

Current density imaging

Electroporation phantom

Current density imaging

Effect of electric pulses

Current density imaging

Current encoding part

Imaging part

CDI calculation

y

B

x

B

x

B

z

B

z

B

y

Bj xyzxyzCDI ,,

1

0

2. Ampere law

1. Phase is proportional to Bz

Thin-sample approximation

tyxByx zCDI ,,

0,,1

0 x

B

y

Bj zzCDI

Electric pulses• Two 20 ms pulses @ 15 V• Eight 100 μs pulses @ 1000 V

Current density imaging

5 10 15 20 25 30

5

10

15

20

25

30

x y

Vector field (jx,jy)

2 4 6 8 10 12 14 16

2

4

6

8

10

12

14

16

51015202530

5

10

15

20

25

30

x

y

Vector field (jx,jy)

246810121416

2

4

6

8

10

12

14

16

Phase image 2D current density field

experiment simulationElectrode setup

MRI of woodOn 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

Formation of the reaction zone

new grown tissues

MRI of wood

Day 8

Day 3

Day 1

MRI of wood

Day 28

Day 14

Day 168

MRI in dental research

root channel

bifurcation

enamel

dentin

pulp

periodontalcommunications

Premolars

1-2 root channels

Molars

3-4 root channels(in the literature was reported even up to 7 root channels)

MRI in dental research

• 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.

Root channels are not clearly visible.

Root channels after endodontic treatment.

MRI in dental research

X-ray imageHard dental tissues are bright on the images, soft tissues cannot be seen.

MR image obtained after co-addition of all slicesSoft 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.