1. Ultrasonic Nonlinear Imaging- Contrast Imaging

2. History 1968 Gramiak et al published observation of echo signal from LV injection of indocyanine dye Subsequent research showed this phenomenon occurred with just about any liquid injected through small needle

3. More History First work was with free gas bubbles –bubbles didn ’ t last very long –size too big to go through lungs, needed intra-arterial injection Late ‘ 80 ’ s - early ‘ 90 ’ s - development of numerous agents –more stable –smaller size

4. Motivation X-ray, CT, nuclear, and MR all need it. Enhance backscatter signal from blood –Blood signal typically 40dB below tissue Provide visualization of low velocity flow normally masked by tissue motion –measure of microvasculature important in many disease states

5. Desired Properties Non-toxic/easily eliminated Able to be injected intravenously Small enough to pass through microcirculation Physically stable Acoustically active

6. Contrast Imaging Contrast agents are used to provide higher contrast. The three commonly seen contrast agents are backscatter, attenuation and sound velocity. Contrast agents could be solid particles, emulsion, gas bubbles, encapsulated gas, or liquid.

7. Contrast Imaging Primary clinical benefits: –Enhanced contrast resolution between normal and diseased tissues. –Outline of vessels or heart chambers. –Tissue characterization by using tissue specific agents. –Increasing blood flow signals. –Dynamic study using washout curve.

8. Example Before injection After injection Harmonic imaging Harmonic Doppler

9. More Examples Bubbles & Physiology Parenchymal phase at 90-120 seconds, can be up to 5 min Arterial phase starts 20-45 seconds after injection Portovenous phase at 45-90 seconds

10. High MI, Harmonic B-mode using Levovist Liver Metastases- primary Breast Ca Pre Post Tumor Detection

11. Coded Harmonic Angio using Levovist Tumor Characterization Focal Nodular Hyperplasia

12. Coded Harmonic Angio using Levovist Tumor Characterization Hepatocellular Carcinoma (HCC)

13. Low MI Harmonic using Sonovue* * Images with non-approved agents for internal GE training only Tumor Characterization

14. Low MI Harmonic - 2 using Definity* * Images with non-approved agents for internal GE training only Early Phase Late Phase Tumor Detection

15. High MI Fundamental Color using Levovist Hemangioma PrePost Tumor Detection/Characterization

16. High MI Harmonic Color using Levovist Tumor Detection Hemangioma?, Adenomatous Nodule?

17. Clinical Values (I) Tumor Detection presence or absence of liver, kidney or pancreatic masses Tumor Characterization avascular- cyst hypovascular- metastasis, hemangioma hypervascular- primary carcinoma, hypervascular met Others enhances vessels for RAS, Carotid stenosis, TCD, etc better visualization of thrombus (IVC, TIPS) post ablation follow up trauma assessment

18. Clinical Values (II) Endocardial border detection. Left ventricle (LV) function. Valvular regurgitation quantification. LV flow patterns. Perfusion area of coronary artery. Assessment of surgery for ventricular septal defect.

19. Clinical Values (III) Liver tumor enhancement. Uro-dynamics and kidney functions. Tubal function and placenta perfusion. Transcranial Doppler enhancement. LV pressure measurements.

20. Current Contrast Agents Aerosomes (ImaRx, Tucson, AZ) Albunex (MBI, San Diego, CA) BY963 (Byk Gulden, Konstanz, Germany) Echovist (Schering, Berlin, Germany) EchoGen (Sonus, Bothell, WA) DMP115 (DuPont-Merck, N. Billerica, MA) Imagent US (Alliance, San Diego, CA) Levovist (Schering, Berlin, Germany) NC100-100 (Nycomed, Oslo, Norway)

21. Current Contrast Agents (Cont.) Optison (MBI, San Diego, CA) approved in US for cardiac Oralex (MBI, San Diego, CA) PESDA (Univ of Nebraska, Omaha, NE) SonoRx (Bracco, Princeton, NJ) US approved oral agent Sonovist (Schering, Berlin, Germany) Sonovue (Bracco, Milan, Italy) ST68 (Drexel Univ, Philadelphia, PA) Quantison (Andaris, Nottingham, UK) Quantison Depot (Andaris, Nottingham, UK) Many more,…

22. Contrast Mechanisms Strong backscattering produced by air bubbles. The backscatter increases roughly linearly with the number of micro-bubbles. A bubble in liquid acts as a harmonic oscillator. Acoustic resonance provides the major echo enhancement. In addition, strong harmonics are produced.

23. Contrast Mechanisms Acoustic attenuation of soft tissues is typically represented by a constant (e.g., 0.5dB/cm/MHz). Since contrast agents significantly change the scattering properties, attenuation measurements can also be used for contrast enhancement.

24. Contrast Mechanisms Sound velocity is primarily determined by density and compressibility. Apparently, micro-bubble based contrast agents alter sound velocity. Contrast enhancement based on sound velocity variations is still academic.

25. Contrast Mechanisms Micro-bubbles produce strong harmonics when insonified near the resonance frequency. If such harmonics are stronger than tissue harmonics, contrast can be improved. Second harmonic signal is most useful due to limited transducer and system bandwidth.

26. (Encapsulated) Gas Bubbles

27. Bubble Characteristics Size RBC 6–8 µm Microbubble 2–8 µm Gas –use high molecular weight, less soluble gas Shell for stabilization –tune for desired acoustic properties

28. Ultrasound-Induced Encapsulated Microbubble Phenomena Oscillation Translation Coalescence Fragmentation Sonic cracking Jetting,…

29. Optical Measurements

31. 100 Mframes/s camera

32. Examples

33. Pressure Dependence of Expansion MI = 0.089 MI = 0.15 MI = 0.39MI = 0.25

34. Variations in Bubbles Reaction

36. Bubble Oscillation

37. Ultrasound-Induced Oscillation Moderate: Alternate expansions and contractions with the same amplitude and duration at low driving pressures (stable cavitation). Violent: At higher pressures, greater bubble expansion amplitude than contraction amplitude, and relatively slow expansion followed rapid contraction (inertial or transient cavitation). Cavitation threshold: Above which the bubble’s maximum radius is larger than twice the equilibrium radius.

38. Modeling Strength of backscatter signal depends on difference in acoustic properties between two materials... p = particle m = surrounding medium For a particle of volume V in homogenous medium  = compressibility  = mass density

39. Modeling Now need to include shell effects... For a shell encapsulated gas bubble of instantaneous radius R:  eff ~ elasticity of shell  = density of surrounding media  tot = total damping coefficient P(t) = incident acoustic energy Accurate only at low pressures

40. Simulations

41. FreeEncapsulated

42. Simulations

43. Measurements

44. Optical Measurements MI = 0.09 MI = 0.67

45. Translation

46. Resulted from primary radiation force (pressure gradient across the bubble surface). Maximal in contraction phase. Used for active targeting.

47. Translation

48. Secondary radiation force: The microbubbles translate toward each other (oscillating bubbles generate spatially varying pressure fields).

49. Coalescence

50. Fusion of two or more bubbles. As bubbles expand, bubble surfaces flattens and thinning occurs. When critical thickness is reached (around 0.1 micron), bubbles rupture and merge with each other.

51. Coalescence

52. Fragmentation

53. Fission of a bubble into smaller bubbles.

54. Fragmentation

55. Sonic Cracking

56. Ultrasound induced formation of a shell defect causing gas to escape from the bubbles. Mechanism not yet known.

57. Jetting

58. During contraction near a boundary, collapse may be asymmetrical.

59. Potential Clinical Applications

60. Interference from Tissue Nonlinearities

61. Non-Linear Response Contrast agents Transmit freq.= f o 2fo2fo fofo Conventional Imaging: Receive freq. = f o Harmonic Imaging: Receive freq. = 2f o

62. Various Contrast Modes High MI B-Mode, Harmonic - optimized for SAE harmonic imaging Low MI B-Mode, Harmonic 1 and 2 - optimized for nondestructive harmonic imaging High MI colorflow fundamental - optimized for SAE destruction effect High MI colorflow harmonic - optimized for SAE with reduced tissue flash artifact

63. Step 1: Xmit 25 Step 2: Step 3: 25 74 Suppress Rcv 27 410 Utilizes Encoding Technique From ‘Coded Harmonics’ To Suppress Fundamental Signal Uses decoding techniques similar to B Flow to separate tissue & contrast signal Coded Harmonic Angio Step 4: 74 Separate Contrast Signal Contrast Agent Tissue Tissue and Contrast

64. Problem: Blood echoes are very weak and sometimes moving too slow for Doppler techniques Detecting Blood Reflectors Blood Tissue Noise

65. Solution: Inject contrast agents to enhance signal Problem: Blood echoes are very weak and sometimes moving too slow for Doppler techniques Detecting Blood Reflectors Agent Noise Tissue

66. Solution: Inject contrast agents to enhance signal Use codes to 1) detect harmonic return signal Problem: Blood echoes are very weak and sometimes moving too slow for Doppler techniques Detecting Blood Reflectors Agent Tissue Noise

67. Solution: Inject contrast agents to enhance signal Use codes to 1) detect harmonic return signal 2) Suppress tissue signal Problem: Blood echoes are very weak and sometimes moving too slow for Doppler techniques Detecting Blood Reflectors Agent Tissue Noise

68. Harmonic Interference In contrast imaging, in which the tissue harmonic signals are un-desirable, the amplitude of the propagating wave needs to minimized. Large apertures (smaller f-numbers) may be used. It was reported that tissue harmonic signal can be reduced by 3dB by doubling the aperture size.

69. Reduction of Interference from Tissue Harmonic cancellation system. Sub-harmonic imaging. Pulse-inversion Doppler (clutter). Pulse-inversion fundamental imaging.

70. Harmonic Cancellation System

71. Aperture Size vs. Harmonic Generation

72. Harmonic Cancellation Using a Pre-biased Signal

75. Sub-Harmonic Imaging

76. Tissue propagation does not generate significant sub-harmonic signals. Sub-harmonic signals may be generated with microbubbles in proper acoustic fields. Sub-harmonic imaging can thus be used for reduction of tissue nonlinear signals.

77. Sub-Harmonic Generation 0.6 MPa, 16 cycles 0.6 MPa, 64 cycles

78. Sub-Harmonic Generation

79. 0.23 MPa, Occurence 0.53 MPa, Growth 1.17 MPa, Saturation

80. Pulse Inversion Doppler (for Clutter Reduction)

81. Pulse Inversion Doppler

82. Pulse Inversion Doppler (Linear)

83. Pulse Inversion Doppler (Non-Linear)

84. Pulse Inversion Doppler

87. Pulse Inversion Fundamental Imaging

88. Effects of Transmission Phase

89. Pulse Inversion Fundamental Imaging