Ultrasound Contrast Agents: Basic Principles and imaging - HD

Introduction to Ultrasound Contrast Imaging

My name is Peter Franking.
I'm a physicist and senior scientist with Bruco Global RD.
I'm going to talk about some basic principles
of ultrasound contrast imaging
among the different diagnostic imaging modalities.

Advantages of Ultrasound Imaging

Ultrasound imaging is a convenient one since it's a bedside
technique, which is non-invasive
and safe with no radiation involved.
This makes it a patient friendly technique.
Moreover, it's cost-effective
and provides real-time information which allows
for dynamic evaluation.
And this can be of particular importance when imaging,
for example, the heart, muscles, tendons and joints.

Anatomical and Functional Information in Ultrasound

As said, ultrasound imaging is typically used
to obtain anatomical information, non-invasively
as shown in the image on the left dough
as shown by the image on the right.
Functional information example related
to blood flow can be obtained at the same time
using doppler techniques.
Nevertheless, Doppler imaging is limited
to providing blood flow, blood flow information
of big vessels, and it's not sensitive enough
to provide profusion information from the smallest,
smallest branches of the vascular system.

Role of Ultrasound Contrast Agents

For this, we need an ultrasound contrast agent,
as is nicely depicted in the image at the bottom
where enhancement at the micro vessels level can be
observed, which is shown simultaneously
with the anatomical be mode image in this side
by side display.
Thus, these contrast agents provide additional diagnostic
information using ultrasound in case we want
to assess tissue profusion.
For example, when comparing normal versus
pathological tissue.
This can be for detecting
and characterizing small lesion based on
perfusion characteristics.
Another interesting application
of these agents is monitoring the efficacy
of anti antigenic treatments where changes
of the microvasculature are evaluated over time.

Key Features of Ultrasound Contrast Agents

So what are the most important features
of these contrast agents?
They consist of micro bubbles,
which are smaller than eight micron in diameter,
and this allows them to pass through the smallest branches
of the lungs so that
after intravenous injection they circulate systemically,
they're stabilized,
and this improves their persistent during the examination
and allow them to persist for about five to 15 minutes.
They remain within the vascular system
after the intravenous injection, so they are considered
to be pure blood pool agents.
They are very echogenic,
meaning there's a strong interaction
between the microbubbles
and the incident ultrasound wave,
and they possess an excellent safety profile.
They can be considered as a useful alternative
for other contrast enhanced imaging modalities.

Bubble Oscillation

To explain why these microbubbles are so echogenic, I'd like
to discuss three physical topics, bubble oscillation,
resonance frequency, and nonlinear oscillation,
Starting with bubble oscillation.
Here we have a schematic representation
of an ultrasound wave and a microbubble.
Because of the size of the microbubbles,
they're much smaller than the wavelength
of the ultrasound wave, and
because they are highly compressible, these bubbles compress
during the positive cycle of the ultrasound wave
and they expand during the negative cycle,
so they oscillate in response
to the incoming ultrasound wave to demonstrate
that this is observed.
In reality here we have a video,
which is a high speed recording
of an oscillating microbubble,
so we can appreciate the strong excursions
of the microbubble wall
and we can see the expression, the expansion,
and the compression phase during oscillation.
Because of these oscillations,
these bubbles scatter the incoming ultrasound wave actively
so they can be considered
as secondary sources of ultrasound.
A physical parameter
to quantify scattering efficiency is the scattering
cross-section, and in the figure here we see the scattering
cross-section as functional frequency.
Now for a typical microbubble, the scattering cross-section
or scattering efficiency increases as functional frequency
until it reaches a peak, then decreases
and reaches a plateau.
Now this peak is typical for a resonator,
so these microbubbles resonate in an ultrasound field.
The frequency at the peak is considered
as the resonance frequency.

Resonance Frequency and Comparison to Solid Particles

Comparing these microbubbles, the scattering cross-section
of these microbubbles with that of a solid particle,
for example, a red blood cell, we first see
that solid particles do not resonate.
Moreover, the scattering cross-section is about 100 million
times lower for the red blood cells
or the solid particles compared
to a microbubble of the same size.
So microbubbles are very effective ultrasound scatterers
compared to solid particles of the same size.
The resonance frequency of ultrasound contrast agents,
which have sizes typically smaller than eight micron
coincide with the frequencies used in ultrasound imaging,
and this is a fortunate coincidence that microbubbles,
which pass through the lungs
after an intravenous injection are resonating
in the frequency range from one to seven megahertz.

Challenges with Conventional Imaging and Contrast Specific Techniques

However, if we would image these microbubbles
with the conventional imaging techniques, we,
it would be very difficult to see any enhancement at
as is shown in the video below.
And this is due to the fact that
although these microbubbles are very echogenic,
the response is still much lower compared to the response
of tissue about 100 times lower.
Simply increasing the concentration does not work.
As you can see in the images below.
If we increase the concentration, microbubbles,
attenuate the ultrasound waves
and introduce shadowing of underlying structures.
As you can see on the right side, on the left side,
we have the image of a left ventricle cavity filled
with bubbles and we can see a good penetration up till
the end of the image.
However, in the other image where the
concentration was substantially increased,
we see a strong enhancement of the bubbles only
in the top of the image.
At the bottom, we have a dropout due to shadowing
of the underlying structures
to deal with this problem.
People have developed contrast specific imaging techniques
where bubble specific signatures are exploited,
which are very effective at low agent concentration,
and at the same time suppress strong tissue echoes.
In the ultrasound image,
one of these bubble specific signatures is
nonlinear oscillation.

Nonlinear Oscillation

In fact, microbubbles oscillate differently
during the positive
and the negative peak of the ultrasound wave.
This is nicely demonstrated in the figure below.
Here we have a streak image which shows bubble excursion
as a function of time,
and as we see there is an asymmetry
between the compression phase
and the expansion phase of the bubble.
While this asymmetry
or non oscillation, how can we exploit those
for contrast specific imaging?

Amplitude Modulation Technique

One example that can be used is amplitude modulation,
which is a multi pulse technique,
and basically two identical pulses are
transmitted only.
The second pulse is a scaled version
of the first one in this particular case,
the second pulse has half the amplitude of the first one.
Now tissue, since it's considered to be linear, its response
to the two pulses will be identical replicas,
which are scaled on receive.
If we compensate for the scaling
and we subtracted two responses, we see that they cancel
and the final signal is zero.
This is different for microbubbles due
to a loss of symmetry.
As you can see now, the two responses are not scaled
replicas, and
after processing, we are left
with a bubble specific signature.
Now, these bubble specific signatures are used
to create contrast specific images.
This is showing in the example below, which is a video
of an SonoVue injection in a pig liver on the left side.
In this dual display configuration, we have the BMO image,
which serves as an anatomical reference.
On the right side, we have our contrast specific image,
and since we are here
before agent injection,
the image is black at the level of the liver.
After injecting the agent, the bubbles appear
and we see the enhancement at the level
of the microvasculature in the liver.
So in this way, we are able
to measure perfusion in the liver.
So contrast specific imaging techniques like amplitude
modulation are very effective in detecting very low
concentration of microbubbles
and suppressing tissue at the same time.

Clinical Applications and Examples

Another example is shown in this light.
Here we have a SonoVue injection in the human liver.
On the right side we have our anatomical information
or our BMO image.
In this particular case,
a hypoechoic lesion was identified in the liver
with the suspicion of focal nodular
hyperplasia, a benign lesion.
On the left side, we have our contrast specific image.
Again, at this time before injection, the image is black
after injection, we see the strong enhancement at the level
of the lesion compared to that
of the surrounding parenchyma.
Moreover, these kind of enhancement dynamics
in the lesion compared to that of the parenchyma can be used
to characterize lesions like this.
And in this particular case, it was confirmed
that this is a focal nodular hyperplasia.

Summary

So in summary, ultrasound contrast agents are made
of suspensions of microbubbles smaller than eight micron,
which allowed them to cross the pulmonary barrier
after an intravenous injection.
These microbubbles are very echogenic
and very effective in scattering ultrasounds in the
diagnostic frequency range compared to solid particles.
And this is mainly due to their resonance
microbubbles exhibit a
specific acoustic signature due to nonlinear oscillations
and contrast specific imaging techniques all exploit these
nonlinear oscillations by detecting individual microbubbles
and suppressing tissue at the same time.