1. Fund BioImag 2012 12-1 12: MRI contrast mechanisms 1.What is the mechanism of T 2 * weighted MRI ? BOLD fMRI 2.How are spin echoes generated ? 3.What are the standard contrast MR sequences ? T 1,T 2 and proton-density weighted MRI 4.By which mechanism do contrast agents act ? After this course you 1.are capable of describing the biophysical basis of BOLD contrast 2.Understand the mechanism of spin echo generation 3.Know the three contrasts that can be generated by the spin echo imaging sequence and how the timing parameters are optimized for each contrast 4.Understand why the same tissue appear bright on T2 weighted images and dark on T1 weighted images 5.Understand the mechanism by which the two principal contrast agent mechanisms lead to signal increase or decrease.

2. Fund BioImag 2012 12-2 MRI: One magnet, many contrast mechanisms FLAIR: T 2 and T 1 weighted (inversion recovery CSF-nulled) [TI=ln2T 1 (CSF)] T 2 -weighted [TE=T 2 (CSF)] T 1 -weighted T 2 -weighted Proton density- weighted Examples of proton density, T 1, and T 2 -weighted images, from the Whole Brain Atlas site at Harvard. Note fluid appearance in all images. Large cyst (just cerebrospinal fluid) Multiple sclerosis T 1 -weighted [TR=T 1 (GM)] T 1 -weighted T 2 -weighted

3. Fund BioImag 2012 12-3 T 2 *-Weighted Images Venography Designed to make venous blood (rich in deoxy- hemoglobin) darker than normal tissue (=reduce magnetization in blood) HypoxiaNormoxia BOLD fMRI=functional MRI

4. Fund BioImag 2012 12-4 Another view on spatial encoding with MRI Let’s give it another try … (compare w. Lesson 11) Slice Select (G z ) Freq. Encode (G) RF 1. Excitation3. Frequency encoding (For G along x) S(t 2 ) and M(x) are linked by FT M(  2 ) = FT{S(t 2 )} = M(x) Linear combination of e.g. G x and G y : G=(G x,G y )=cos  G,sin  G M(x) is Radon transform measured along the direction of the Gradient G TE Measure Radon Transforms along  (as in CT) every TR s (T 1 relaxation) (→ sinogram, projection reconstruction, see also central slice theorem) Phase Encode (G y ) GyGy t2t2 n  G y  =G y n  GyGy   Define t 1 =n  S(t 1,t 2 ) M(  1,  2 )=M(y,x) Phase encoding is just frequency encoding in a 2 nd time dimension 2. Phase encoding 2D FT

5. Fund BioImag 2012 12-5 12-1. Gradient echo imaging T 2 * weighting – static dephasing Slice Select (G z ) Freq. Encode (G x ) RF Signal °° TE Phase Encode (G y ) Static field imperfection M xy summed over voxel Empirically: NB. T 2 >T 2 * NB.  B(r)TE=  n  B(r)[TE/n]

6. Fund BioImag 2012 12-6 Deoxy-hemoglobin : paramagnetic oxy-Hb : diamagnetic B0B0 oxyRBC deoxyRBC Blood Oxygenation Level Dependent (BOLD) Biophysical basis of T 2 * changes Magnetic susceptibility  : magnetic field in object depends on object properties  <0: diamagnetism (repelling force)  >paramagnetism (attracting force) z De-Oxygenated capillary  oxygenated capillary  oxy ~ -0.3  deoxy ~ 1.6  B 0 in tissue T 2 * increases with decreased tissue deHb concentration depends on venous architecture in the imaging voxel

7. Fund BioImag 2012 12-7 Blood oxygen level dependent (BOLD) contrast measures deHb content Brain physiology: O 2 consumption increases less than Flow during “thinking” What is the consequence? Saturation=%oxy-Hb (deHB=100%-saturation) steady-state hemodynamic response ↑ cerebral blood flow (CBF) : ↓ dHb : ↑ BOLD ↑ cerebral blood volume (CBV) : ↑ dHb : ↓ BOLD venuoles arterioles capillary bed artery vein 1-2 cm 50  m 0510152025 seconds fMRI signal (T 2 *) -5 0 5 1.0 1.5 2.0 2.5 % signal change

8. Fund BioImag 2012 12-8 T 2 *-weighted Image Average Difference Image Statistical Significance Image Thresholded Statistical Image Overlay on Anatomic Image functional MRI (fMRI): Brain Activation Analysis Time series task fMRI signal OFF ON Statistical analyses (lots)

9. Fund BioImag 2012 12-9 T 2 * is subject to magnetic susceptibility differences (B 0 imperfections, e.g. air-tissue interface, implants) Ear canal sinus T 2 * -weighted image Gradient echo (TE~T 2 * ) How to minimize these effects? Signal of gradient echo ~ e -TE/T2* Solution I: Minimize TE Gradient echo (TE<<T 2 * ) implant Solution II: Use SPIN ECHO (see next) But, T 2 - weighing is needed for contrast… Tissue: diamagnetic Air (O 2 ): paramagnetic

10. Fund BioImag 2012 12-10 TE/2 abc d spin echo 90 x 180 y a b c d 12-2. (Hahn) spin echo echo formation using  RF pulse Gradient G y (t) Dephasing Rephasing Real (y) Imaginary (x) 180 0 RF pulse (along y) Observation: When using two RF pulses, echo occurs at twice the time difference between the RF pulses (constant gradient G). Magnetization before & after 180: M  (sin  cos ,) → M  (-sin , cos  )  =  G y yTE/2)

11. Fund BioImag 2012 12-11 Spin echo formation Mathematical formulation GxGx TE RF (B 1 ) flip angle  1234 Magnetization at the time points specified: 1: (0,0,M z ) rotated by  degrees (RF pulse): 2: (0,M z sin ,M z cos  )  (0,M y,…) [only consider M xy, precesses with B = +  G x x 3: M y (cos[(+  G x x)t], sin[(+  G x x)t])  M y [cos(+  x ), sin(  x )] 180 0 pulse about x inverts y component of M xy : M y → - M y 4: M y [cos(+  x ), -sin(  x )]  M y [cos(  x ),sin(-  x )]  identical to the effect of a negative gradient (see previous lecture)  echo formation 180 0 S~M xy TE T 2 (Spin echo) T 2 * (gradient echo) Signal S decays exponentially due to T 2 or T 2 * relaxation Unavoidable (B 0 is never homogenous in space) exploited in BOLD fMRI

12. Fund BioImag 2012 12-12 The spin echo imaging sequence Slice Select (G z ) Freq. Encode (G x ) RF Signal S 90° TE Phase Encode (G y ) 180° Repeated every TR seconds Derivation of signal S  M xy : Proton density   M 0

13. Fund BioImag 2012 12-13 12-3. Basic MRI contrast mechanisms I. Proton density weighted MRI Short TE: minimize influence of T 2 Imaging the number of protons per voxel  Tissues with higher spin density (e.g., fat, CSF) have higher image intensity Water content: only ~70-100% (poor contrast) Minimize effects of relaxation: long TR: minimize effect of T 1 differences

14. Fund BioImag 2012 12-14 II. T 2 contrast contrast based on differences in T 2 T 2 weighting: long TR → reduced T 1 effects longer TE : accentuate T 2 differences What TE is optimal? 1.Find TE at which M xy is most strongly affected by T 2 differences 2.Solution (variational calculus, Lecture 1): 3.Find TE at which dM xy /dT 2 =maximal 4.For tissues with different T 2a and T 2b : Use TE between the two T 2 values. TE = T 2

15. Fund BioImag 2012 12-15 III. T 1 -weighted MRI: contrast based on differences in T 1 1.use short TR to maximize the differences in longitudinal magnetization during the return to equilibrium 2.Tissues with shorter T 1 have higher image intensity 3.Question: When is the signal maximally sensitive to changes/differences in T 1 ? T 1 weighting: short TE → minimize T 2 effects short TR → accentuate T 1 effects Answer: TR=T 1 (see 9-17)

16. Fund BioImag 2012 12-16 , T 1 and T 2 weighted MRI Spin echo images T 2 weighted  weighted T 1 weighted TR 510ms TE 14ms TR 4500 ms TE 15ms TR 4500ms TE 105ms Note fluid appearance in all images. Same subject lipoma T 1 -weighted MRI of the knee fat bone fat has short T 1 compared to muscle NB. Water in tissues: short-T 1 ↔ short T 2 long-T 1 ↔ long T 2

17. Fund BioImag 2012 12-17 T 2 -weighted MRI of cancer (cancer tissue water has long T 2 ) Colon carcinoma metastases (liver) T 2 -weighted TR = 500 ms TE = 14 ms TR = 2 s TE = 40 ms nude mouse with xenograft tumor (D282 tumor) T 1 -weighted T 2 -weighted T 1 -weighted post-contrast

18. Fund BioImag 2012 12-18 12-4. MRI Contrast Agents shorten relaxation times Relaxivity r 1, r 2 * Mechanism: (interaction with water & molecular tumbling) TR T 1 (T 1 -weighted) T 1 CA S~M z Example: [CA]=1mM, r 1 =3 mM -1 s -1 and T 1 =1s: 1/T 1 CA =1+3=4 → T 1 CA =0.25s Contrast agent w. concentration. [CA] shortens T 1 : (TE<<T 2 ) TE T 2 * (gradient echo) T 2 *CA S~M xy 1) T 1 – Paramagnetic agents 2) T 2 – Paramagnetic and Susceptibility agents [T 2 * – Susceptibility agents] brighter signal on T 1 -weighted images Example: [CA]=1mM, r 2 *=50 s -1 mM -1 and T 2 *=50ms: 1/T 2 * CA =20+50=4 → T 2 * CA =14ms Reduced (removed) signal on T 2 or T 2 *-weighted images

19. Fund BioImag 2012 12-19 Examples I Gd Enhanced Brain Malignancy Negative Contrast From Iron Oxide (T 2 * agent) MRI contrast agents Typically restricted to blood –Ideal to image vessels –Leaky vessel walls » Tumours » Inflammation pre post MRI of mouse trunk

20. Fund BioImag 2012 12-20 Examples II: Intracellular contrast agents Mn-enhanced MRI (MEMRI) Manganese (paramagnetic): –Transported by Ca channels –Shortens T 1 Mn-enhanced MRI (synaptic activity imaging) Transplanted Langerhans islets in liver Imaging stem cells, transplanted cells Cells pre-loaded with contrast agent