Ultrasonic Nonlinear Imaging- Contrast Imaging

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Ultrasonic Nonlinear Imaging-Contrast Imaging
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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

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More History

• First work was with free gas bubbles
• bubbles didnt last very long
• size too big to go through lungs, needed
  intra-arterial injection

• Late 80s - early 90s - development of
  numerous agents
• more stable
• smaller size

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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

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Desired Properties

• Non-toxic/easily eliminated

• Able to be injected intravenously

• Small enough to pass through microcirculation

• Physically stable

• Acoustically active

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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.

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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.

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Example
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More Examples
Bubbles Physiology
Portovenous phase at 45-90 seconds
Parenchymal phase at 90-120 seconds, can be up
to 5 min
Arterial phase starts 20-45 seconds after
injection
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Tumor Detection
Liver Metastases- primary Breast Ca
Post
Pre
High MI, Harmonic B-mode using Levovist
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Tumor Characterization
Focal Nodular Hyperplasia
Coded Harmonic Angio using Levovist
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Tumor Characterization
Hepatocellular Carcinoma (HCC)
Coded Harmonic Angio using Levovist
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Tumor Characterization
Low MI Harmonic using Sonovue
Images with non-approved agents for internal GE
training only
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Tumor Detection
Late Phase
Early Phase
Low MI Harmonic - 2 using Definity
Images with non-approved agents for internal GE
training only
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Tumor Detection/Characterization
Hemangioma
Pre
Post
High MI Fundamental Color using Levovist
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Tumor Detection
Hemangioma?, Adenomatous Nodule?
High MI Harmonic Color using Levovist
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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

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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.

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Clinical Values (III)

• Liver tumor enhancement.
• Uro-dynamics and kidney functions.
• Tubal function and placenta perfusion.
• Transcranial Doppler enhancement.
• LV pressure measurements.

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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)

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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,

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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.

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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.

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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.

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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.

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(Encapsulated) Gas Bubbles
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Bubble Characteristics

• Size

• Shell for stabilization
• tune for desired acoustic properties

• Gas
• use high molecular weight, less soluble gas

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Ultrasound-Induced Encapsulated Microbubble
Phenomena

• Oscillation
• Translation
• Coalescence
• Fragmentation
• Sonic cracking
• Jetting
• ,

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Optical Measurements
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Optical Measurements
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Optical Measurements
100 Mframes/s camera
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Examples
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Pressure Dependence of Expansion
MI 0.089
MI 0.15
MI 0.39
MI 0.25
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Variations in Bubbles Reaction
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Variations in Bubbles Reaction
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Bubble Oscillation
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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 bubbles
  maximum radius is larger than twice the
  equilibrium radius.

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Modeling

• Strength of backscatter signal depends on
  difference in acoustic properties between two
  materials...

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Modeling

• Now need to include shell effects...

For a shell encapsulated gas bubble of
instantaneous radius R
Keff elasticity of shell r density of
surrounding media
dtot total damping coefficient P(t)
incident acoustic energy
Accurate only at low pressures
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Simulations
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Simulations
Free
Encapsulated
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Simulations
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Measurements
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Optical Measurements
MI 0.09
MI 0.67
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Translation
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Translation

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

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Translation
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Translation

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

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Coalescence
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Coalescence

• 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.

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Coalescence
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Fragmentation
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Fragmentation

• Fission of a bubble into smaller bubbles.

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Fragmentation
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Sonic Cracking
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Sonic Cracking

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

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Jetting
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Jetting

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

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Potential Clinical Applications
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Interference from Tissue Nonlinearities
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Non-Linear Response
Contrast agents
Transmit freq. fo
fo
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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

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Coded Harmonic Angio

• Step 1

Tissue and Contrast
Utilizes Encoding Technique From Coded
Harmonics To Suppress Fundamental Signal
Step 2
Step 3
Uses decoding techniques similar to B Flow to
separate tissue contrast signal
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Detecting Blood Reflectors
Problem Blood echoes are very weak and
sometimes moving too slow for Doppler techniques
Tissue
Blood
Noise
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Detecting Blood Reflectors
Problem Blood echoes are very weak and
sometimes moving too slow for Doppler techniques
Solution Inject contrast agents to enhance
signal
Tissue
Agent
Noise
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Detecting Blood Reflectors
Problem Blood echoes are very weak and
sometimes moving too slow for Doppler techniques
Solution Inject contrast agents to enhance
signal Use codes to 1) detect harmonic return
signal
Agent
Tissue
Noise
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Detecting Blood Reflectors
Problem Blood echoes are very weak and
sometimes moving too slow for Doppler techniques
Solution Inject contrast agents to enhance
signal Use codes to 1) detect harmonic return
signal 2) Suppress tissue signal
Agent
Tissue
Noise
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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.

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Reduction of Interference from Tissue

• Harmonic cancellation system.
• Sub-harmonic imaging.
• Pulse-inversion Doppler (clutter).
• Pulse-inversion fundamental imaging.

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Harmonic Cancellation System
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Aperture Size vs. Harmonic Generation
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Harmonic Cancellation Using a Pre-biased Signal
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Harmonic Cancellation Using a Pre-biased Signal
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Harmonic Cancellation Using a Pre-biased Signal
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Sub-Harmonic Imaging
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Sub-Harmonic Imaging

• 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.

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Sub-Harmonic Generation
0.6 MPa, 16 cycles
0.6 MPa, 64 cycles
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Sub-Harmonic Generation
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Sub-Harmonic Generation
0.23 MPa, Occurence
0.53 MPa, Growth
1.17 MPa, Saturation
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Pulse Inversion Doppler (for Clutter Reduction)
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Pulse Inversion Doppler
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Pulse Inversion Doppler (Linear)
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Pulse Inversion Doppler (Non-Linear)
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Pulse Inversion Doppler
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Pulse Inversion Doppler
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Pulse Inversion Doppler
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Pulse Inversion Fundamental Imaging
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Effects of Transmission Phase
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Pulse Inversion Fundamental Imaging
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Pulse Inversion Fundamental Imaging
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Pulse Inversion Fundamental Imaging
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Pulse Inversion Fundamental Imaging
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Pulse Inversion Fundamental Imaging