1. Basic principles and application in Medicine Basic principles and application in Medicine October, 2008 J.Brnjas-Kraljević

2. 6 October 2003 The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2003 jointly to Paul C Lauterbur and Peter Mansfield for their discoveries concerning "magnetic resonance imaging" The Nobel Assembly at Karolinska Institutet The Nobel Assembly at Karolinska Institutet Paul Lauterbur (born 1929), Urbana, Illinois, USA, discovered the possibility to create a two-dimensional picture by introducing gradients in the magnetic field. By analysis of the characteristics of the emitted radio waves, he could determine their origin. This made it possible to build up two-dimensional pictures of structures that could not be visualized with other methods. Peter Mansfield ( born 1933 ), Nottingham, England, further developed the utilization of gradients in the magnetic field. He showed how the signals could be mathematically analyzed, which made it possible to develop a useful imaging technique. Mansfield also showed how extremely fast imaging could be achievable. This became technically possible within medicine a decade later.

3. Glossary  magnetic field – field intensity – tesla (T) Earths magnetic field <70  T – in medicine 0,5 – 3,0 T  homogeneous  homogeneous – the same intensity in each space point  constant  constant – unchangeable intensity upon time  radiofrequent  radiofrequent – frequency of regular change of magnetic field intensity, in medicine 100 kHz – 10 GHz  field gradient  field gradient – regularity in the field intensity changes in linear dimensions of the space - (T/m) – in medicine is better if more steep – 30 mT/m (0,3 mT/cm)  pulse  pulse – is the measure of energy transfer to the system – time interval of RF-magnetic field that transferees the energy on spin system and induces excitation

4.  nuclear spin  nuclear spin – intrinsic property of the material particle – describes the magnetic property of nuclei with odd number of nucleons, in medicine nuclei with spin number ½ ; determines number of possible energy states in magnetic field: if ½ than two energy states  magnetic moment  magnetic moment – physical parameter - the measure of magnetic properties of nuclei with spin; the base of NMR  resonance characteristic frequency  resonance – process of maximal energy transfer between two systems – described by characteristic frequency  relaxation characteristic time  relaxation – processes by which the excited system is after ending of perturbation returned to the ground energy state – described by characteristic time

5. Magnetic Resonance  measured are magnetic properties of atomic nuclei in sample placed in the strong external magnetic field  - the changes in the state of the system are controlled resonant absorption - resonant absorption  - the processes of returning to the equilibrium are followed relaxation emission – relaxation emission spectroscopy method  if the structure of molecules is determined - it is spectroscopy method spectroscopy  in medical diagnostic - as spectroscopy (MRS) or imaging as imaging (MRI)

6. History  1944. F.Bloch i E.Purcell – nuclear magnetic resonance  1971. R. Damadian – differentiates T 1 i T 2 in tumors  1973. P.Lauterbur – the first MRI  1975. R.Ernst – distinguishing the signals by phase and frequency - presentation by Fourier transform – the base of all modern MRI  1977. P. Lauterbur – independent by R.Damadian – MRI of the whole body  P.Mansfield – echo method (EPI) – 5 min/image – today 5 s/image  1986. NMR microscopy – resolution 10  m in volume of 1 cm 3  1987. EPI method – cardiac cycles in real time  C. Dumoulin – angiography - MRA – without contrast agents  1993. functional MRI  1995. spectroscopy in vivo  1998. combination with other imaging methods  2003. N.P. to P. Lauterbur and P. Mansfield

7.  What is NMR ?  What is MRI?  What is fMRI?  What is looked at, what is seen, what is measured?  How is it measured?

8. We are interested in we measure cell macromolecules and water water molecules water molecule Hydrogen atom Hydrogen nucleus volume of heterogenic tissue

9. Interaction of the nuclear magnetic moment of hydrogen nuclear magnetic moment of hydrogen and magnetic field  hydrogen nucleus has spin – its magnetic properties are described by magnetic moment, , magnetic moment, , and intrinsic magnetic field parallel antiparallel  in external magnetic field magnetic moment experience two possible states: parallel or antiparallel to the field direction – we talk about two possible states of energy  the volume of hydrogen placed outside the magnetic field – magnets are randomly oriented in space – volume is not magnetized

10.  the same volume in the external magnetic field – energy states occupancy is determined by Boltzmann, s distribution  – there is more nuclei parallel to the field – volume is magnetized  the top of single magnetic moment precesses in magnetic field with Larmor frequency, because of giromagnetic constant characteristic for the nucleus

11. B0B0 M0M0 no magnetic field - randomly oriented magnetic macroscopic moments - no macroscopicmagnetization homogeneous, constant magnetic field B 0 more magnetic moments are in the magnetic macroscopic magnetization field direction - macroscopic magnetization in the direction of B 0 field is measured Very important: nuclei, atoms or molecules are not oriented, but magnetic moments ! It can be visualized like:

12. macroscopic magnetization  ordered state of equilibrium system in the magnetic field is described by - macroscopic magnetization in the direction of the magnetic field resonance  process of resonance will be realized by energy equal to the difference of the two states and it will promote more nuclei in the higher energy state – resulting in change of amount and direction of macroscopic magnetization  this process is realized with the energy of radiofrequent magnetic field - frequency being characteristic for the observed nucleus  when the RF-field frequency is equal to Larmor-frequency of the nucleus the interaction of magnetic moment and the field changes the Boltzmann, s distribution  higher the difference of occupancy in the equilibrium more precise are the measurements of the resonance

13.  direction of the vector or – the visualization of two possible energy states of magnetic moment in B 0 field  difference in occupancy is bigger for the field of higher intensity  macroscopic magnetization  macroscopic magnetization is bigger for bigger difference quant energy h will be absorbed if  E = h  that is the value of the field where the signal is measured Theory – quantum physics

14. nucleus number of protons neutrons spin  / MHz/T 1H1H1H1H1 0 1/2 99,98 42,58 2H2H 1 1 0,015 6,54 31 P0 1 17,25 23 Na 2 1 3/2 11,27 14 N 1 1 3,08 13 C0 1 10,71 19 F 0 1 40,08 1/2 100 1,11 100 0,015 0,0004 0,0024 0,094 abundance biological abundance 1/2100 0,63 Properties of the nucleus natural abundance - fraction of isotope in the element biological abundance – fraction of the element in the tissue

15. Resonance condition  E = E +1/2 - E -1/2  states separation:  E = E +1/2 - E -1/2 depends on external magnetic field  by absorption of energy quant higher energy state  basic relation of magnetic resonance  =  B 0  – Larmor frequency

16. Radiofrequent magnetic field B 1  resonance absorption of time dependent magnetic field energy B 1 (t)=B 1maxis sin  t  B 1 is perpendicular to B 0, and magnetic induction is 10 -4 B 0  B 1 frequency = Larmor frequency of atomic nucleus B1B1B1B1 B0B0 M0M0

17.   = const.  the same nuclei have different Larmor frequency if in different magnetic fields  if the inhomogeneity of the field is controlled – the base of NMR as imaging method B 0 = const.  different nuclei have different Larmor frequency, because  differ  in spectra their lines are separated  B 0

18. process of relaxation  by end of excitation the system returns to the equilibrium state defined by Boltzmann distribution – process of relaxation  two mechanisms of relaxation – both are the source of information on dynamic properties of the system  in magnetic resonance - 4 basic parameters: - macroscopic magnetization, - chemical shift, - relaxation time T 1, - relaxation time T 2 Relaxation

19. nuclear magnetic moment – bar magnet B 0 = 0 – because of Brownian motion randomly oriented B 0  0 - magnetic moments precess with Larmor frequency around field direction: more are in + Z, less in – Z direction phase of precession are different: macroscopic magnetization is in magnetic field B 0 direction; no component in perpendicular plane absorption of RF- field energy, forces the macroscopic magnetization to simultaneous precession about the axes of both fields the motion is represented by spiral path from Z axis to XY plane and towards –Z axis Quasiclassical model

20. Macroscopic magnetization  sample in B 0 is magnetized  in the direction of magnetic field (axis +Z) macroscopic magnetization M 0 is measured - determined by: and has only longitudinal component  and expressed by measurable parameters:

21. hence, macroscopic magnetization  increases with increasing magnetic field strength: good instruments work on higher fields  is inversely proportional with temperature: the best is to measure on law temperatures, unsuitable in medical applications  depends on density of nuclear spins of interest: in medicine hydrogen from water molecules (free or bound) and there is plenty of them in tissues; or hydrogen in fat

22. Appearance of transversal magnetization transversal magnetization,M xy  in equilibrium no transversal magnetization, M xy, because of different precession phases of magnetic moments  the action of magnetic field B 1 forces the equalization of the phases and the appearance of transversal magnetization  because of resonance energy absorption the longitudinal component is decreasing, M z < M 0 MzMz M0M0 M xy z x y B0B0 B1B1

23.  in NMR experiment always transversal magnetization is measured – as the induced electromotor force in detector coil  detector is placed in X-axis  amount of M z i M xy depends on length of field B 1 action. The angle of decline from +Z is:   the amount of energy transferred on the system by the radiofrequent field is named pulse

24. Characteristic pulses  /2 pulse  magnetization is rotated in Y- axis  pulse  magnetization is rotated in Z -axis z x y z x y

25. Chemical shift  observed nucleus is in B 0 field not naked but in atom, so it feels local magnetic fields of surrounding electrons - mainly from own atom B eff = B 0 - B loc = B 0 (1-  )     - shielding - depends on chemical composition of molecules of observed nuclei  effective field is always smaller than B 0, because of diamagnetic effect of electron  eff =  (B 0 - B loc )  hence, there is the shift in resonant frequency for the same nuclei in static magnetic field, but in different molecules  that is chemical shift, - defined by standard sample (ppm)

26. chemical shift in water and fat difference in resonant frequency is only 1 kHz for 42 MHz, but enough to differ that two molecules molecules are in the same static magnetic field signal area is proportional to the number of resonating nuclei

27.  intrinsic – defined by chemical surrounding of the nucleus  induced – defined by the surrounding of the molecule - solvent, pH, temperature, paramagnetic centers, secondary and tertiary structure in proteins, denaturation of proteins, different pathological processes spectroscopy in vivo  diagnostic value in spectroscopy in vivo  B 0 - B loc ) CH CH2 CH3 frekvencija/ Hz CH CH 2 CH 3

28. Relaxation processes – relaxation times  relaxation processes relies the energy in surrounding decrease of system energy  interchange of energy among the observed nuclei increase of entropy  both processes are determined by dynamic properties of the system  in biological systems tissue differ in relaxation parameters  processes are effective - signal of resonance is constantly measurable, despite the small difference in energy state abundance  processes of relaxation are random therefore described by exponential function with characteristic times  relaxation parameters – relaxation times T 1 i T 2

29. Spin-lattice relaxation - T 1  energy absorbed in the spin-system is released into the local magnetic field – induced by rotation of surrounding molecules  rotation is defined by correlation time:   c ~ 10 -11 s for small molecule  rot big   c ~ 10 -8 s for big molecule  rot small   (Larmor frequency)  in surrounding of big molecules the relaxation of the spin-system is faster  T 1 shorter  in plain water relaxation is slow  T 1 longer  T 1 depends on temperature and viscosity of surrounding – it is the measure of molecular motion  tissues have different T 1

30. Determination of T 1  -  -  /2 Determination of T 1 -  -  -  /2  applying  pulse  longitudinal magnetization is changed from - M 0 to + M 0 :  T 1 is determined from T1T1 M 0 (1-2e -1 )

31.  applying  /2 pulse  longitudinal magnetization increases from 0 to +M 0  T 1 is determined from

32. Inversion recovery - IR  longitudinal magnetization is by 180° pulse turned into Z- direction and than returns to equilibrium value  by 90° pulse applied before completed relaxation the transversal magnetization is proportional to the amount of relaxed spins  in detector coil FID is induced  intensity of Fourier transform after one measurement is S = k r ( 1 - 2e -TI/T1 )  and after repetition S = k r ( 1 - 2e -TI/T1 + e -TR/T1 ) TR – time of repetition TI – time between pulses TI signal

33.  / 2 pulsa  magnetization is by 90 o pulse rotated into XY plane  returns into equilibrium  in detector coil FID is measured  intensity of FT signal depends on time between pulses – TR

34. T 1 and T 2 tissueT 1 /sT 2 /ms hydrogen density CSF0,8 - 20 110 - 2000 70 - 230 white matter 0,76 – 1,08 61 - 100 70 - 90 gray matter 1,09 – 2,15 61 - 109 85 - 125 membrane 0,5 – 2,2 50 - 165 5 - 44 muscle 0,95 – 1,82 20 - 67 45 - 90 fat 0,2 – 0,75 53 - 94 50 - 100

35. Spin-spin relaxation - T 2  by termination of radiofrequency magnetic field action the magnetic moments interchange the energy  because of small inhomogeneities of magnetic field Larmor frequencies are different – phases of precession starts to differ  transversal magnetization decreases exponentially  interchange of energy between spins is greater if the nuclei are closer and less movable - T 2 is considerably shorter in solid state  tissues have different T 2  for each nucleus in certain surrounding T 2  T 1

36. Determination of T 2  applying  /2 pulse  the disappearance of transversal magnetization is measured  T 2 is determined from

37. Spin - Echo  / 2,   to determine T 2 most used method is spin-echo:  / 2,   signal height depends on time between pulses (TE) and on repetition time (TR) TE

38. How is spin-echo built  90° pulse induces transversal magnetization  it diminishes - moments are dephasing because of different  - FID  after the time interval of  the 180° pulse along Y –axis induces the phase coherence again after interval of 2   this is the echo signal

39. Bloch equations  clasical presentation of macroscopic magnetic moment movement in the magnetic fields  bases for T 1 and T 2 calculations

40. Relations of T 1 and T 2  in plain water T 1  T 2 ~ 3 s  tumor tissue has more water - T 1 longer than for healthy tissues  in solid state T 1 ~ min - h ; T 2 ~ 10 -6 s  differences in relaxation times adequate for contrast enhancement in MRI  different sequences of pulses  necessary to repeat the sequence because the signals are very small  by good choice of field strength and sequence of pulses the contrast of the tissues can be amazing although the density of the observed tissues is practically the same

41. Contrasts in MRI  biological parameters are the relaxation times  T 1 i T 2 are main parameters for production of contrasts  by adjustment of time interval between pulses  i  /2  for measurements the interval producing the biggest difference between measured signals from different tissues is chosen  further improvement of contrasts by changing the intervals between sequences T 1A T 1B T 2B T 2A sl.10.

42. T 1 - source of contrasts T 1 - source of contrasts  -  -  /2  T 1 difference source of contrast: sequence  -  -  /2   - pulse flips the magnetization in Z- direction  after time interval , M z is greater for tissue with shorter T 1 M z,short > M z,long   /2 pulse flips that component into XY - plane: M xy,short > M xy,long  in detector coil the measured signal (S): S(M xy,short ) > S(M xy,long )   is chosen so to satisfy M xy,short -M xy,long = max

43. T 2 - source of contrasts T 2 - source of contrasts  /2 -  -   T 2 difference - source of contrast: sequence  /2 -  -  - the appearance of spin echo (Hahn 1950)   /2 pulse flips the magnetization into XY- plain  after time interval , M xy is bigger for tissue with longer T 2 M xy,long > M xy,short   pulse rephrases spins S j  after  - signal of spin echo – S j dependent on   in detection coil measured signal: S j (M xy,long ) > S j (M xy,short )   must satisfy M xyd -M xyk = max

44. Contrast T2T2 T1T1 r tissueT 1 /sT 2 /ms hydrogen density gray matter 1,09 – 2,15 61 - 109 85 - 125 white matter 0,76 – 1,08 61 - 100 70 - 90 CSF0,8 - 20 110 - 2000 70 - 230 fat 0,2 – 0,75 53 - 94 50 - 100 muscle 0,95 – 1,82 20 - 67 45 - 90 skin 0,5 – 2,2 50 - 165 5 - 44

45. MR spectroscopy (MRS )  in medicine we use nuclei with magnetic moment - in characteristic molecules of tissues  spectral lines belong to chosen nuclei in different molecules or atomic groups  spectra display chemical shift for the small volume excited in the tissue  changes in the place and/or intensity of lines or the appearance of new lines point at metabolic and structural changes

46. Spectroscopy in vivo - PRESS Spectroscopy in vivo point resolved spectroscopy - PRESS  with adequately chosen gradients of magnetic field B 0 in X-, Y- and Z-direction we measure the signals from small volume  spectrum is display of chemical shifts  the concentration of single aminoacid can be determined  the structure of small volume is determined  in combination with imaging - fMRI

48. Magnetic resonance instrument  constant and homogeneous magnetic field - electromagnet or superconductive magnet  in science - up to 14 T; in medicine – up to 2,3 T  radiofrequent magnetic field - frequency 600 MHz, or 64 MHz - induced in coil  intensity of B 1 is 10 -4 B 0  detection coil + computer registration U RF generator signal detector B0B0 B1B1

49. Fourier transform mathematical procedure - enables differentiation of frequencies shortens the time of signal detection enables huge number of repetition measurements