U.S. patent application number 12/562935 was filed with the patent office on 2011-06-16 for methods for acquisition and display in ultrasound imaging.
Invention is credited to Desmond Hirson, Kai Wen Liu, James Mehi, Andrew Needles, Jerrold Wen, Christopher A. White.
Application Number | 20110144494 12/562935 |
Document ID | / |
Family ID | 42039061 |
Filed Date | 2011-06-16 |
United States Patent
Application |
20110144494 |
Kind Code |
A1 |
Mehi; James ; et
al. |
June 16, 2011 |
METHODS FOR ACQUISITION AND DISPLAY IN ULTRASOUND IMAGING
Abstract
In general, the invention provides methods for use in the
acquisition and display of ultrasound images. In particular, the
invention provides methods for displaying ultrasound images using a
persistence algorithm, gating ultrasound acquisition based on
subject respiration, triggering ultrasound acquisition based on
subject ECG, and destroying bubble contrast agents during imaging.
The methods may be employed with any suitable ultrasound
system.
Inventors: |
Mehi; James; (Thornhill,
CA) ; White; Christopher A.; (Toronto, CA) ;
Needles; Andrew; (Toronto, CA) ; Wen; Jerrold;
(Thornhill, CA) ; Liu; Kai Wen; (North York,
CA) ; Hirson; Desmond; (Thornhill, CA) |
Family ID: |
42039061 |
Appl. No.: |
12/562935 |
Filed: |
September 18, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61192690 |
Sep 18, 2008 |
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61192661 |
Sep 18, 2008 |
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Current U.S.
Class: |
600/441 |
Current CPC
Class: |
Y10T 29/49169 20150115;
A61B 8/14 20130101; Y10T 29/49005 20150115; A61B 8/13 20130101;
Y10T 29/49156 20150115; A61B 8/543 20130101; H01L 41/29 20130101;
Y10T 29/42 20150115; B06B 1/0622 20130101 |
Class at
Publication: |
600/441 |
International
Class: |
A61B 8/14 20060101
A61B008/14 |
Claims
1. A method for frame persistence implemented by an ultrasound
imaging system, comprising: a. obtaining a plurality of frames of
ultrasound at a baseline frame rate (FR.sub.0); b. processing a
portion of the plurality of frames of ultrasound at a processing
rate (PR), wherein the portion comprises a first frame comprising a
first plurality of data points; c. applying a persistence routine
to at least one of the first plurality of data points, wherein the
persistence routine combines the at least one of the first
plurality of data points with a corresponding stored data point
based on a user defined persistence setting, FR.sub.0, and PR, to
produce at least one persistence processed data point; d. storing
the at least one persistence processed data point to replace the
stored data point of (c); and e. generating a persistence processed
output frame from the at least one persistence processed data
point.
2. The method of claim 1, wherein the persistent routine comprises:
y(n)=(1-(1-.alpha.).sup.p)x(n)+(1-.alpha.).sup.py(n-1), where p is
the ratio FR.sub.0/PR, .alpha. is the user defined persistence
setting and is greater than 0 and less than 1, n is the frame
index, y(n) is the persistence processed data point, x(n) is the at
least one of the first plurality of data points, and y(n-1) is the
corresponding stored data point, wherein the value of y(n-1) is set
to 0 for n=1.
3. The method of claim 1, wherein the plurality of frames comprises
B-Mode data, Color Flow image data, or Power Doppler image
data.
4. The method of claim 1, further comprising displaying the
persistence processed output frame on a display.
5. The method claim 1, further comprising repeated steps (c)-(e)
with subsequent frames.
6. A method for destroying contrast agent bubbles present in a
region of interest of a subject, comprising: (a) providing the
subject to which has been administered contrast agent bubbles; (b)
scanning the region of interest in the subject with ultrasound; (c)
receiving a bubble destruction command; (d) transmitting at least
one ultrasound pulse into the region of interest, wherein the
ultrasound pulse is transmitted at a mechanical index sufficient to
destroy bubbles in the region of interest; and (e) resuming
scanning of the region of interest.
7. The method of claim 6, wherein the region of interest comprises
one or more focal zones, and the ultrasound pulse of step (d) is
transmitted into each focal zone.
8. The method of claim 6, wherein the mechanical index of step (c)
is greater than about 0.6.
9. The method of claim 6, wherein step (d) comprises operating at
10-20 MHz with a 4 cycle pulse, with a plurality of focal zones
evenly spaced over a depth of the region of interest (ROI), at 100%
TX power at a mechanical index (MI) greater than 0.6, wherein 10-20
MHz pulses are fired at a Pulse Repetition Frequency (PRF) of 25
kHz and above for up to 1 s.
10. The method of claim 6, wherein scanning of the region of
interest is discontinued between steps (b) and (c).
11. The method of claim 6, wherein ultrasound employed in steps (b)
and (e) has a wider bandwidth than ultrasound employed in step
(d).
12. The method of claim 6, wherein the ultrasound employed in steps
(b) and (e) is produced by one transducer, and the ultrasound
transmitted in step (d) is produced by a different transducer.
13. The method of claim 6, wherein a single transducer is employed
in steps (b), (d), and (e).
14. The method of claim 6, wherein step (e) comprises monitoring
for reperfusion of bubble contrast agent into the region of
interest.
15. The method of claim 6, wherein step (e) comprises monitoring
for determining the circulating amount of bubble contrast
agent.
16. A method for respiration gating during ultrasound imaging,
comprising: acquiring a respiration signal from a subject;
determining a start of a respiration cycle in the respiration
signal; setting a valid zone based on the start of the respiration
cycle and user defined offset and/or duration; acquiring a
plurality of frames of ultrasound; discarding one or more frames of
the plurality of frames acquired outside the valid zone; and
outputting remaining frames of the plurality of frames acquired
inside the valid zone.
17. The method of claim 16, wherein acquiring a plurality of frames
comprises acquiring the plurality of frames at an acquisition rate
of at least 200 frames per second.
18. The method of claim 16, wherein each of the acquired plurality
of frames are time-stamped to indicate when each frame is
acquired.
19. A method for ECG triggered acquisition during ultrasound
imaging, comprising: (a) acquiring, at a host computer, an ECG
signal from a subject; (b) determining, at the host computer, an
R-wave point in the ECG signal; (c) determining, at the host
computer, a trigger point threshold and a trigger slope based on
the R-wave point; (d) transferring the trigger point threshold and
the trigger slope to a programmable logic device; and (e)
triggering, by the programmable logic device, the acquisition of
ultrasound based on the trigger point threshold and the trigger
slope.
20. The method of claim 19, wherein triggering based on the trigger
point threshold and the trigger slope is used to acquire a cineloop
that starts at a specified point in a cardiac cycle and runs for a
specified number of cardiac cycles.
21. The method of claim 19, wherein triggering based on the trigger
point threshold and the trigger slope is used to acquire one or
more of B-Mode data, Color Doppler Mode data, Power Doppler Mode
data, Contrast Mode data, and 3D Mode data.
22. The method of claim 19, further comprising: (i) acquiring a
respiration signal from a subject; (ii) determining a start of a
respiration cycle in the respiration signal; (iii) setting a valid
zone based on the start of the respiration cycle and user defined
offset and/or duration; (iv) discarding ultrasound acquired outside
the valid zone during step (e); and (v) outputting ultrasound
acquired inside the valid zone during step (e).
23. The method of claim 22, wherein ultrasound is acquired at a
rate of at least 200 frames per second.
24. The method of claim 22, wherein ultrasound frames are
time-stamped to indicate when each frame is acquired.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application Nos. 61/192,690 and 61/192,661, both filed Sep. 18,
2008 and both of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to the field of high frequency
ultrasound imaging systems.
SUMMARY OF THE INVENTION
[0003] The invention provides various methods for use in the
acquisition and display of ultrasound imaging. The methods are
preferably employed in conjunction with high frequency ultrasound
imaging using an arrayed transducer.
[0004] In one aspect, the invention features a method for frame
persistence implemented by an ultrasound imaging system by
obtaining a plurality of frames of ultrasound at a baseline frame
rate (FR.sub.0); processing a portion of the plurality of frames of
ultrasound at a processing rate (PR), wherein the portion includes
a first frame having a first plurality of data points; applying a
persistence routine to at least one of the first plurality of data
points, wherein the persistence routine combines the at least one
of the first plurality of data points with a corresponding stored
data point based on a user defined persistence setting, FR.sub.0,
and PR, to produce at least one persistence processed data point;
storing the at least one persistence processed data point to
replace the previously stored data point; and generating a
persistence processed output frame from the at least one
persistence processed data point. The persistent routine is for
example:
y(n)=(1-(1-.alpha.).sup.p)x(n)+(1-.alpha.).sup.py(n-1),
where p is the ratio FR.sub.0/PR, .alpha. is the user defined
persistence setting and is greater than 0 and less than 1, n is the
frame index, y(n) is the persistence processed data point, x(n) is
the at least one of the first plurality of data points, and y(n-1)
is the corresponding stored data point, wherein the value of y(n-1)
is set to 0 for n=1. The plurality of frames may include B-Mode
data, Color Flow image data, or Power Doppler image data. The
method may further include displaying the persistence processed
output frame on a display. The method may also be repeated for
subsequent frames.
[0005] The invention further features a method for destroying
contrast agent bubbles by providing a subject to which has been
administered contrast agent bubbles; scanning a region of interest
in the subject with ultrasound; receiving a bubble destruction
command; transmitting at least one ultrasound pulse into the region
of interest, wherein the ultrasound pulse is transmitted at a
mechanical index sufficient to destroy bubbles in the region of
interest (e.g., greater than about 0.6); and resuming scanning of
the region of interest. The region of interest may include one or
more focal zones, and the destruction of bubble may occur in each
focal zone. A specific bubble destruction sequence of ultrasound
includes transmission at 10-20 MHz with a 4 cycle pulse, with a
plurality of focal zones evenly spaced over a depth of the region
of interest (ROI), at 100% TX power at a mechanical index (MI)
greater than 0.6, wherein 10-20 MHz pulses are fired at a Pulse
Repetition Frequency (PRF) of 25 kHz and above for up to 1 s. In
various embodiments, scanning of the region of interest is
discontinued prior to bubble destruction. Alternatively, the
mechanical index of ultrasound transmission is increased in
response to the bubble destruction command, while scanning the
region of interest. The ultrasound employed in scanning may have a
wider bandwidth than ultrasound employed in bubble destruction.
Scanning of the region of interest and bubble destruction may occur
using the same or different transducers. After bubble destruction,
the method may include monitoring for reperfusion of bubble
contrast agent into the region of interest or monitoring for
determining the circulating amount of bubble contrast agent, e.g.,
when the contrast agent is targeted to a particular tissue.
[0006] The invention also features a method for respiration gating
during ultrasound imaging by acquiring a respiration signal from a
subject; determining a start of a respiration cycle in the
respiration signal; setting a valid zone based on the start of the
respiration cycle and user defined offset and/or duration;
acquiring a plurality of frames of ultrasound, e.g., at an
acquisition rate of at least 200 frames per second; discarding one
or more frames of the plurality of frames acquired outside the
valid zone; and outputting remaining frames of the plurality of
frames acquired inside the valid zone. The acquired plurality of
frames may also be time-stamped to indicate when each frame is
acquired.
[0007] The invention further features a method for ECG triggered
acquisition during ultrasound imaging by acquiring, at a host
computer, an ECG signal from a subject; determining, at the host
computer, an R-wave point in the ECG signal; determining, at the
host computer, a trigger point threshold and a trigger slope based
on the R-wave point; transferring the trigger point threshold and
the trigger slope to a programmable logic device; and triggering,
by the programmable logic device, the acquisition of ultrasound
based on the trigger point threshold and the trigger slope, e.g.,
at a rate of at least 200 frames per second. The method may be
employed to acquire a cineloop that starts at a specified point in
a cardiac cycle and runs for a specified number of cardiac cycles.
The method may be used to acquire one or more of B-Mode data, Color
Doppler Mode data, Power Doppler Mode data, Contrast Mode data, and
3D Mode data.
[0008] Any of the methods of the invention may be employed with
each other and with any of the ultrasonic systems described herein.
The methods are particularly useful in high frequency ultrasound
imaging (greater than 20 MHz) and/or in imaging small animals.
[0009] Additional advantages of the invention will be set forth in
part in the description which follows, and in part will be obvious
from the description, or may be learned by practice of the
invention. The advantages of the invention will be realized and
attained by means of the elements and combinations particularly
pointed out in the appended claims. It is to be understood that
both the foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive of the invention, as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows an exemplary respiration waveform 4200 from a
subject where the x-axis represents time in milliseconds (ms) and
the y-axis represents voltage in millivolts (mV).
[0011] FIG. 2 shows a valid acquisition zone where the start of the
respiration cycle combined with the user's specifications denotes
the valid acquisition zone.
[0012] FIG. 3 illustrates an exemplary method for respiration
gating.
[0013] FIG. 4 illustrates an exemplary method of ECG triggered
acquisition.
[0014] FIG. 5 illustrates one of various methods that exist to
detect the R-Wave events on an ECG signal.
[0015] FIG. 6A shows unfiltered ECG data with a high degree of DC
variance.
[0016] FIG. 6B shows filtered ECG data with the DC variance
effectively removed.
[0017] FIG. 6C illustrates an exemplary single pulse of ECG data
showing a threshold trigger point and a blank period.
DETAILED DESCRIPTION OF THE INVENTION
[0018] In general, the invention provides methods for use in the
acquisition and display of ultrasound images. In particular, the
invention provides methods for displaying ultrasound images using a
persistence algorithm, gating ultrasound acquisition based on
subject respiration, triggering ultrasound acquisition based on
subject ECG, and destroying bubble contrast agents during imaging.
The methods may be employed with any suitable ultrasound system. An
exemplary system is disclosed in U.S. Publication No. 2007/0239001.
Suitable ultrasound systems are also available from VisualSonics,
Inc. (VEVO.RTM. 2100).
Persistence Processing
[0019] Typically, persistence processing combines information from
previous frames of B-Mode detected data with the most recent frame
of B-Mode detected data to produce an output frame. Persistence can
also be applied to other data sets such as Color Flow or Power
Doppler overlays or image data processed with harmonic imaging
methods. A persistence algorithm is applied to each data point in
the image. An equation used to apply persistence is:
y(n)=.alpha.x(n)+(1-.alpha.)y(n-1) Eq. 1
where 0<.alpha.<1, n is the frame index, y(n) is the new
persisted output value, x(n) is the new incoming data point, and
y(n-1) is the previous persisted output value. Data represented by
x(n) and y(n) have the same spatial coordinates, which have been
left out for clarity. The parameter .alpha. is selected for each
specific persistence setting (e.g. "low", "med", "high", etc.) in
order to impart the desired degree of persistence to the displayed
data. If .alpha. is 1.0, then no persistence is applied. For low,
medium and high persistence, typical settings for .alpha. are in
the ranges 0.71 to 0.99, 0.31 to 0.7 and 0.01 to 0.3
respectively.
[0020] For small animal imaging and other high frequency
applications, the B-Mode acquisition frame rates may vary over a
wide range, for example from less than 100 frames per second (fps)
to approximately 500 frames per second. During real time
acquisition and display of data, otherwise known as "live
scanning," it may be necessary to decimate the frames prior to
processing and display. All acquisition frames can be saved in an
RF buffer. Data transfer bandwidth over busses from hardware to a
host machine, for example, PCI express or ethernet, is limited, and
the total number of acquisition frames may not be able to be
transferred in real time to the host machine. For example, the
hardware might acquire frames at 300 fps (acquisition frame rate),
but, if the data transfer rate is 100 fps, then during live
scanning only every third frame is processed. The difference in the
time of acquisition of sequential frames that are processed by the
persistence algorithm will vary depending on the number of frames
that are skipped. In some cases, it is desirable that the amount of
persistence applied be approximately constant relative to the
acquisition time frame. For example, during live scanning, frames
acquired at 300 fps designated F1, F2, F3, F4, . . . have
acquisition times of 0, 3.33, 6.67, 10, 13.33, 16.67, . . .
milliseconds relative to the start time. Because of data transfer
restrictions, every third frame is transferred and processed, so
frames F1, F4, F7, . . . etc. will undergo persistence processing.
The time of acquisition of the frames being persistence processed
during live scanning will then be 0, 10, 20, . . . milliseconds,
and the acquisition rate of the data set being processed is 100
frames per second. If, once live scanning is halted, all acquired
frames that had been saved in RF Buffer are transferred
sequentially, the frames being persistence processed will have
acquisition times of 0, 3.33, 6.67, 10, 13.33, 16.67, . . .
milliseconds.
[0021] Equation 1 can be modified so that that regardless of
whether all acquisition frames are processed or some frames are
skipped, the frames corresponding to equivalent acquisition times
have the approximately the same amount of persistence applied.
[0022] In Equation 1, y(n) can also be expressed as the convolution
of x(n) with a function h(n):
y(n)=.alpha.x(n)*h(n) Eq. 2,
where h(n)=(1-.alpha.).sup.n, * is the convolution operator, and n
is the frame index.
[0023] The factor .alpha. may be chosen for each persistence
setting for a baseline frame rate (FR.sub.0). If the acquisition
rate of the data set being processed (PR) is different from the
baseline rate FR.sub.0 by a factor p, i.e., p=FR.sub.0/PR, the
signal x(n) that is undergoing processing is effectively resampled
at a lower rate, that is, it is decimated by a factor p. The
function h(n) must then be replaced by the function
h'=(1-.alpha.).sup.pn, and the persistence algorithm becomes:
y(n)=persistScale.alpha.x(n)+(1-.alpha.).sup.py(n-1) Eq. 3
where p is the ratio FR.sub.0/PR, and persistScale is the ratio of
the areas under the functions h(n) and h'(n) given by
persistScale = k = 0 .infin. ( 1 - .alpha. ) k k = 0 .infin. ( 1 -
.alpha. ) kp = 1 - ( 1 - .alpha. ) p .alpha. . Eq . 4
##EQU00001##
[0024] For example, for a "med" persistence setting and a baseline
frame rate of 300 fps, the value for .alpha. is selected as 0.5. If
the data are processed and displayed at a rate of 100 fps, the
persistence algorithm is:
y ( n ) = 1 - ( 1 - 0.5 ) 3 0.5 ( 0.5 ) x ( n ) + ( 1 - 0.5 ) 3 y (
n - 1 ) . Eq . 5 ##EQU00002##
[0025] Typically, all data in a frame are subjected to the
persistence processing, but, in certain embodiments, only a portion
of the data is subjected to the processing. It will also be
appreciated by one skilled in the art that the above method of
applying persistence to frames of data which may have variable
processing rates may be applied to any such data, e.g., Color Flow
image data and Power Doppler image data.
Respiration Gating
[0026] The invention also features a method of gating ultrasound
acquisition based on the respiration waveform of a subject,
typically a small animal. FIG. 1 shows an exemplary respiration
waveform 4200 from a subject where the x-axis represents time in
milliseconds (ms), and the y-axis represents voltage in millivolts
(mV). A typical respiration waveform 4200 includes multiple peak
positions or plateaus 4202, one for each respiration cycle of the
subject. As shown in FIG. 1, a reference line 4204 can be inserted
on the waveform 4202. The portions of the respiration waveform 4200
above the reference line 4204, are peaks or plateaus 4202, and
generally represent the period when the subject's movement due to
breathing has substantially stopped. By "substantially stopped" is
meant that a subject's movement due to breathing has stopped to the
point at which the collection of ultrasound data is desirable
because of a reduction in artifacts and inaccuracies that would
otherwise result in the acquired image due to breathing motion. A
subject's motion due to breathing substantially stops for a period
of approximately 100 to 2000 milliseconds during a respiration
cycle. The period during a subject's respiration cycle during which
that subject's motion due to breathing has substantially stopped
may vary depending on several factors including, animal species,
body temperature, body mass, or anesthesia level.
[0027] The invention features a method for gating retention of
ultrasound based on the respiration cycle. For example, a threshold
value can be selected, and a time position can be recorded when the
respiration signal exceeds the threshold. When the signal falls
below the threshold again, a second time position can be recorded.
The highest signal value between these two points can denote a peak
position. The peak position can indicate the start of the
respiration cycle. The user can specify additional information such
as a custom offset from the start of the cycle. The user can also
specify a duration during which to allow acquisition. As shown in
FIG. 2, the start of the respiration cycle combined with the user's
specifications denotes a valid acquisition zone, e.g., when frames
can be acquired without motion artifact.
[0028] Frames can be continuously acquired at a high rate.
Following acquisition, each frame can be tested to determine if the
frame was acquired during the valid period. If not, the frame can
be discarded. An exemplary method for respiration gating is
illustrated in FIG. 3. At 4400, a respiration signal is acquired
from an animal. At 4402, the respiration signal is processed. At
4403, a start of a respiration cycle is determined from the
processed respiration signal. At 4404, one or more user supplied
values, such as a requested offset, a duration, and the like, is
received. The one or more user supplied values allows the user to
control the timing of a valid region of acquisition within a
respiration cycle. At 4405, the start of the respiration cycle and
the one or more user supplied values is used to define a valid
region. At 4406, frames can be continuously acquired at an
acquisition rate. The acquisition rate can be, for example, 200
frames per second. Each frame can be time-stamped to indicate when
the frame is acquired. At 4407, frames that are acquired outside
the valid zone can be discarded. At 4408, frames acquired inside
the valid region are output.
[0029] The respiration waveform 4200 including the peaks 4202 can
be determined by the respiration detection software from electrical
signals delivered by ECG electrodes which can detect muscular
resistance when breathing. For example, muscular resistance can be
detected by applying electrodes to a subject's foot pads. By
detecting changes in muscular resistance in the foot pads, the
respiration detection software can generate the respiration
waveform 4200. Thus, variations during a subject's respiration
cycle can be detected, and ultrasound data can be acquired during
the appropriate time of the respiration cycle when the subject's
motion due to breathing has substantially stopped. For example,
ultrasound data samples can be captured during the approximate 100
milliseconds to 2000 millisecond period when movement has
substantially ceased. A respiration waveform 4200 can also be
determined by the respiration detection software from signals
delivered by a pneumatic cushion (not shown) positioned underneath
the subject. Use of a pneumatic cushion to produce signals from a
subject's breathing is known in the art. A respiration waveform can
be produced with a strain gauge plethysmograph. Methods for
detecting respiration waveforms are also known in the art, e.g., as
described in U.S. Publication No. 2006/0241446.
[0030] The respiration detection software can convert electrical
information from the ECG electrodes (or other detector) into an
analog signal that can be transmitted to the ultrasound system. The
analog signal can be further converted into digital data by an
analog-to-digital converter, which can be included in a signal
processor or can be located elsewhere, after being amplified by an
ECG/respiration waveform amplifier. In one embodiment, the
respiration detection element can comprise an amplifier for
amplifying the analog signal for provision to the ultrasound system
and for conversion to digital data by the analog-to-digital
converter. Using digitized data, respiration analysis software
located in a memory can determine characteristics of a subject's
breathing including respiration rate and the time during which the
subject's movement due to respiration has substantially
stopped.
[0031] Cardiac signals from the electrodes and the respiration
waveform signals can be transmitted to an ECG/respiration waveform
amplifier to condition the signals for provision to an ultrasound
system. It is recognized that a signal processor or other such
device may be used instead of an ECG/respiration waveform amplifier
to condition the signals. If the cardiac signal or respiration
waveform signal from the electrodes is suitable, then use of the
amplifier is unnecessary.
ECG Triggered Acquisition
[0032] ECG triggered acquisition can be used to acquire and display
images at a specified point in a cardiac cycle. ECG triggered
acquisition can also be used to acquire a cineloop that starts at a
specified point in the cardiac cycle and runs for a specified
number of cardiac cycles. ECG triggered acquisition is supported,
for example, in B-Mode, Color Doppler Mode, Power Doppler Mode,
Contrast Mode, 3D Mode, etc. In one aspect, ECG triggered
acquisition can be combined with respiration gating, e.g., as
described herein or in U.S. Publication No. 2006/0241446.
[0033] Generally, there are two components to ECG triggered
acquisition: software signal processing and hardware triggering.
Software signal processing determines the trigger threshold and
slope from an incoming physiological ECG signal, while hardware
triggering uses the slope and threshold to perform the actual
triggering in real time. This method permits a complicated
algorithm to be executed on a host computer, while a very small but
fast segment is run on the hardware.
[0034] An exemplary method of ECG triggered acquisition is
illustrated in FIG. 4. At step 4500, an ECG signal is acquired from
a subject, e.g., a small animal. At step 4502, the signal is
processed, e.g., according to a detection algorithm. At step 4503,
a R-Wave point is identified in the ECG signal. Various methods
exist to detect R-Wave events on an ECG signal. An exemplary method
is described here. Other methods may be used as would be understood
by one skilled in the art. The operations are shown in FIG. 5.
[0035] In FIG. 5, an incoming ECG signal 45100 is first filtered
using a band-pass FIR filter 45101 with a pass band between 100 Hz
and 200 Hz. Other frequency bands may be used depending on the
application (for example, in a human the ECG rate is much slower
than a small animal and these values may be modified). Filtering
effectively removes most of the DC offset. FIGS. 6A and 6B show the
pre and post filtered signal.
[0036] The detection algorithm can use a threshold detection scheme
with a dynamically updating threshold value. Each value in the
filtered ECG signal stream is then tested to determine if it is
above a threshold value 45102. If the value exceeds the threshold
4504, this point is marked as the start of a region (labelled as
"Start" in FIG. 6C). Stream values are tested to determine when the
value drops below the threshold 45105. If the value drops below the
threshold 45106, this point is marked as the end of the region
45107 (labelled as "Stop" in FIG. 6C).
[0037] The maximum value is then found between the start and stop
points of the region 45108. This point is the peak value and is
thus the R-Wave position 4509 (labelled as "Peak" in FIG. 6C). The
slope value may be obtained around the start point.
[0038] A period of about 60 ms measured from the start of the first
threshold detection can be skipped to eliminate any possible
subsequent peaks from being detected too close to the pulse 45110.
This is called the Blank Period as labeled in FIG. 6C. The duration
of the blank period may depend on the time between R-Wave
positions. For example, a small animal with a high heart rate may
use a short blank period (for example, 30-90 ms). A larger animal,
such as a human, with a slower heart rate may employ a longer blank
period (for example 100-600 ms).
[0039] The current threshold point is updated based on the new peak
value 45111. The threshold can be set, for example, at about 80% of
the peak value.
[0040] Returning to FIG. 4, at step 4504, user supplied values are
collected. These user supplied values can include, for example, a
requested offset from the R-Wave to perform triggering. Multiple
trigger points may be selected. At step 4505, a trigger threshold
is determined, and a slope is calculated using the detected R-Wave
points. In one aspect, the trigger threshold is selected to be
about 80 percent of the peak of the R-Wave, although other values
can be selected, for example, 70 percent or 90 percent. The slope
can be determined as the slope of the ECG signal at the threshold
point on the leading edge of the signal. At step 4506, the
calculated slope and the trigger threshold are transferred to
hardware. The calculated slope and trigger threshold values are
updated in real time approximately once per second. Updating the
calculated slope and trigger threshold values allow for accounting
of changes to the ECG signal. At step 4507, the hardware performs
triggering based on threshold and slope information. In another
aspect, the hardware can also trigger based on a peak detection
method or use an external trigger. At step 4508, the trigger event
can be delayed by a user specified amount of time, or multiple
triggers may be enabled. Each subsequent trigger can be delayed by
a different user specified amount of time. At step 4509, it is
determined which mode is used for ECG triggered acquisition,
single-frame acquisition or cineloop acquisition. Depending on the
ECG triggered acquisition mode, the trigger is used differently. If
single-frame acquisition is used, then at step 4510 a single frame
of data is acquired. If at step 4509 it is determined that cineloop
acquisition is used, then at step 4511 a cineloop is acquired. The
length of the cineloop is a user specified number of cardiac
cycles. At step 4512, the acquired data are processed and
displayed.
Bubble Destruction
[0041] Contrast agents, such as microbubbles, can be used in
high-frequency ultrasound imaging. For example, U.S. Publication
2006/0078501, hereby incorporated by reference, describes systems
and methods for the use of microbubbles in ultrasound imaging.
[0042] Disruption-replenishment techniques typically use a
continuous infusion of microbubble contrast agents, generally with
a syringe pump. While the agent is flowing through the imaging
plane, high power ultrasound is applied, which clears the imaging
plane of microbubbles by disrupting (destroying) them. The
subsequent refilling of the agent into the imaging plane can be
tracked over time, giving functional information about the
perfusion of tissue, namely the blood flow (slope of refill) and
blood volume (plateau level). This type of functional information
is valuable to the pre-clinical researcher studying differences in
the perfusion of normal and diseased tissues.
[0043] A different approach to imaging microbubbles pre-clinically
is to use the contrast agent as a marker of a particular disease
state. This is accomplished by attaching (targeting) microbubbles
to endothelial cells of blood vessels that express a surface marker
indicative of the disease state. After allowing microbubbles to
circulate for an appropriate time, e.g., at least 4 minutes, the
targeted signal in a region of interest can be quantified. Then
disrupting the microbubbles and performing another quantification,
gives the signal level of residual freely circulating untargeted
microbubbles. This allows a normalization of the measurement so
that the amount of targeted signal, proportional to the level of
cell surface marker being targeted, is accurately quantified.
[0044] In another embodiment, the bubble contrast agent
compositions can be disrupted or popped by the ultrasound energy at
a given frequency. As used throughout, "disrupted" or "destroyed"
means that a microbubble is fragmented, ruptured, or cracked such
that gas escapes from the microbubble. The compositions may be
disrupted by ultrasound at a frequency at or above 15 MHz, 20 MHz,
30 MHz, 40 MHz, 50 MHz or 60 MHz. The destruction or popping
creates a means of probing perfusion of selected tissues or a means
for releasing a therapeutic payload. It will be understood that
destruction of 100% of bubbles in a given region of interest is not
necessary. An exemplary level of disruption is at least 75%, 80%,
85%, 90%, 95%, or even 99%.
[0045] In one aspect, bubble destruction can be performed with
embodiments described herein using a high-frequency arrayed
transducer. One method includes scanning a region of interest using
an ultrasound system equipped with an arrayed transducer. The
region of interest is divided into one or more focal zones. A
bubble destruction command provided to the ultrasound system causes
scanning of the region of interest to discontinue and a pulse of
ultrasound, e.g., having a narrower bandwidth than the scanning
ultrasound and having a mechanical index, e.g., greater than 0.6,
sufficient to destroy the bubbles, is transmitted into each focal
zone, thereby destroying the bubbles. Scanning of the region of
interest can then resume, e.g., to measure the rate of reperfusion
with additional contrast agent or the background level of contrast
agent. In an alternative approach, scanning is not discontinued,
but rather the bubble destruction command results in an increase in
mechanical index of the transmitted ultrasound, thereby
transmitting a pulse into each focal zone and destroying the
bubbles. Scanning transmission power can then be re-set to a lower
mechanical index. In yet another embodiment, two different
transducers are employed: one is used for scanning, and the other
is used to destroy bubbles.
[0046] For example, embodiments as described herein can perform
bubble destruction by initiating bubble destruction while imaging
in Contrast Mode, by receiving a bubble destruction command (e.g.,
by pressing a key or entering a command into an ultrasound system).
In one exemplary approach, embodiments of systems described herein
stop scanning and the transmit (TX) beamformer is reconfigured to
Burst Mode. In Burst Mode the receive (RX) beamformer is disabled
(there is no image data being collected). In one aspect, Burst Mode
operates at 10-20 MHz (regardless of the transducer being used),
with a narrowband (e.g., 4 cycle) pulse, with a plurality (e.g., 4)
of focal zones evenly spaced over the depth of the region of
interest (ROI), at 100% TX power at high mechanical index
(MI>0.6). Burst Mode fires 10-20 MHz pulses at a Pulse
Repetition Frequency (PRF) of 25 kHz and above for the duration
specified by the user (e.g., up to a max of 1 s). There are 4
pulses per image line to make up the 4 TX foci. After the specified
duration is over, the TX beamformer is reconfigured for the prior
state of Contrast Mode, and the system resumes imaging.
[0047] In another exemplary approach, embodiments of systems
described herein continue scanning in Contrast Mode after bubble
destruction is initiated, however, the TX power is set to 100% for
the duration specified by the user (e.g., up to a max of 1 s), and
the transmit pulse may become more narrowband. All other imaging
parameters remain the same. After the specified duration is over,
the TX power is reset to the prior setting of Contrast Mode, and
the system continues imaging.
[0048] In yet another exemplary approach, embodiments of systems
described herein stop scanning, and both the transmit TX and RX
beamformer are disabled (there is no image data being collected).
Embodiments of systems described herein trigger an external device
such as a low frequency ultrasound therapy unit delivering energy
at, for example, 1 MHz. In one aspect this external device can be a
SoniGene.TM.. The external device (e.g., SoniGene) destroys bubbles
for the duration specified by the user (e.g., up to a max of 1 s).
After the specified duration is over the SoniGene stops
transmitting, the TX and RX beamformers are reconfigured to the
prior state of Contrast Mode, and the system resumes imaging.
[0049] A typical contrast agent comprises a thin flexible or rigid
shell composed of albumin, lipid or polymer confining a gas such as
nitrogen or a perfluorocarbon. Other examples of representative
gases include air, oxygen, carbon dioxide, hydrogen, nitrous oxide,
inert gases, sulfur fluorides, hydrocarbons, and halogenated
hydrocarbons. Liposomes or other microbubbles can also be designed
to encapsulate gas or a substance capable of forming gas as
described in U.S. Pat. No. 5,316,771. In another embodiment, gas or
a composition capable of producing gas can be trapped in a virus,
bacteria, or cell to form a microbubble contrast agent.
[0050] A contrast agent can be modified to achieve a desired volume
percentage by a filtering process, such as by micro or
nano-filtration using a porous membrane. Contrast agents can also
be modified by allowing larger bubbles to separate in solution
relative to smaller bubbles. For example, contrast agents can be
modified by allowing larger bubbles to float higher in solution
relative to smaller bubbles. A population of microbubbles of an
appropriate size to achieve a desired volume percentage can
subsequently be selected. Other means are available in the art for
separating micron-sized and nano-sized particles and can be adapted
to select a microbubble population of the desired volume of
submicron bubbles such as by centrifugation. The number of micro
and nanobubbles of differing sizes can be determined, for example,
using an optical decorrelation method. The diameter of micro and
nanobubbles making up given volume percentage can also be
determined and the number percentage of micro and nanobubbles at
different sizes can also be determined. For optical decorrelation
methods a Malvin.TM., Zetasizer.TM. or similar apparatus may be
used.
[0051] Microbubble contrast agent may also produce nonlinear
scattering when contacted by ultrasound at a frequency above 30
MHz, 40 MHz, 50 MHz or 60 MHz. Non-linear scattering can be
measured, for example, as described in U.S. Publication No.
2006/0078501. Further, transducer operating frequencies
significantly greater than those mentioned above are also
contemplated.
Uses
[0052] Among many possible applications, the described embodiments
may be used in conjunction with visualization, assessment, and
measurement of anatomical structures and hemodynamic function in
longitudinal imaging studies of small animals. The systems can
provide images having very high resolution, image uniformity, depth
of field, adjustable transmit focal depths, multiple transmit focal
zones for multiple uses. For example, the ultrasound image can be
of a subject or an anatomical portion thereof, such as a heart or a
heart valve. The image can also be of blood and can be used for
applications including evaluation of the vascularization of tumors.
The systems can be used to guide needle injections.
[0053] The described embodiments can also be used for human
clinical, medical, manufacturing (e.g., ultrasonic inspections,
etc.) or other applications where producing an image at a transmit
frequency of 15 MHz or higher is desired.
Ultrasound Systems
[0054] As stated, the methods of the invention may be employed with
any suitable ultrasound system, such as those described in U.S.
Publication No. 2007/0239001 and the VEVO.RTM. 2100. Suitable
systems can include one or more of the following: an array
transducer that can be operatively connected to a processing system
that may be comprised of one or more of signal and image processing
capabilities; digital transmit and receive beamformer subsystems;
analog front end electronics; a digital beamformer controller
subsystem; a high voltage subsystem; a computer module; a power
supply module; a user interface; software to run the beamformer; a
scan converter, and other system features as described herein.
[0055] An arrayed transducer used in the system can be incorporated
into a scanhead that, in one embodiment, may be attached to a
fixture during imaging which allows the operator to acquire images
free of the vibrations and shaking that usually result from "free
hand" imaging. A small animal subject may also be positioned on a
heated platform with access to anesthetic equipment, and a means to
position the scanhead relative to the subject in a flexible manner.
The scanhead can be attached to a fixture during imaging. The
fixture can have various features, such as freedom of motion in
three dimensions, rotational freedom, a quick release mechanism,
etc. The fixture can be part of a "rail system" apparatus, and can
integrate with the heated mouse platform.
[0056] The systems can be used with platforms and apparatus used in
imaging small animals including "rail guide" type platforms with
maneuverable probe holder apparatuses. For example, the described
systems can be used with multi-rail imaging systems, and with small
animal mount assemblies as described in U.S. Pat. No. 7,133,713;
U.S. Pat. No. 6,851,392, U.S. Pat. No. 7,426,904, and U.S.
Publication No. 2005/0215878, each of which are each fully
incorporated herein by reference.
[0057] Small animals can be anesthetized during imaging and vital
physiological parameters such as heart rate and temperature can be
monitored. Thus, an embodiment of the system may include means for
acquiring ECG and temperature signals for processing and display.
An embodiment of the system may also display physiological
waveforms such as an electro-cardiogram (ECG), respiration or blood
pressure waveform.
Ultrasound
[0058] Any of the methods of the invention are compatible with
systems adapted to receive ultrasound signals having a frequency of
at least 15 megahertz (MHz) with a transducer having a field of
view of at least 5.0 millimeters (mm) at a frame rate of at least
20 frames per second (fps). In other embodiments, the ultrasound
signals can be acquired at an acquisition rate of 50, 100, or 200
(fps). Optionally, ultrasound signals can be acquired at an
acquisition rate of 200 frames per second (fps) or higher. In other
examples, the received ultrasound signals can be acquired at a
frame rate within the range of about 100 fps to about 200 fps. In
some exemplary aspects, the length of the transducer is equal to
the field of view. The field of view can be wide enough to include
organs of interest such as the small animal heart and surrounding
tissue for cardiology, and full length embryos for abdominal
imaging. In one embodiment, the two-way bandwidth of the transducer
can be approximately 50% to 100%. Optionally, the two-way bandwidth
of the transducer can be approximately 60% to 70%. Two-way
bandwidth refers to the bandwidth of the transducer that results
when the transducer is used both as a transmitter of ultrasound and
a receiver--that is, the two-way bandwidth is the bandwidth of the
one-way spectrum squared.
[0059] The processing unit produces an ultrasound image from the
acquired ultrasound signal(s). The acquired signals may be
processed to generate an ultrasound image at display rate that is
slower than the acquisition rate. Optionally, the generated
ultrasound image can have a display rate of 100 fps or less. For
example, the generated ultrasound image has a display rate of 30
fps or less. The field of view can range from about 2.0 mm to about
30.0 mm. When a smaller field of view is utilized, the processing
unit can acquire the received ultrasound signals at an acquisition
rate of at least 300 frames per second (fps). In other examples,
the acquisition rate can be 50, 100, 200 or more frames per second
(fps).
[0060] In one embodiment, in which a 30 MHz center frequency
transducer is used, the image generated using the disclosed systems
may have a lateral resolution of about 150 microns (.mu.m) or less
and an axial resolution of about 75 microns (.mu.m) or less. For
example, the image can have an axial resolution of about 30 microns
(.mu.m). Furthermore, embodiments according to the present
invention transmit ultrasound that may be focused at a depth of
about 1.0 mm to about 30.0 mm. For example, the transmitted
ultrasound can be focused at a depth of about 3.0 mm to about 10.0
mm. In other examples, the transmitted ultrasound can be focused at
a depth of about 2.0 mm to about 12.0 mm, of about 1.0 mm to about
6.0 mm, of about 3.0 mm to about 8.0 mm, or of about 5.0 mm to
about 30.0 mm.
Transducers
[0061] In various embodiments, the transducer can be, but is not
limited to, a linear array transducer, a phased array transducer, a
two-dimensional (2-D) array transducer, or a curved array
transducer. A linear array is typically flat, i.e., all of the
elements lie in the same (flat) plane. A curved linear array is
typically configured such that the elements lie in a curved plane.
The transducers described herein are "fixed" transducers, meaning
that the transducer array does not utilize movement in its
azimuthal direction during transmission or receipt of ultrasound in
order to achieve its desired operating parameters, or to acquire a
frame of ultrasound data. Moreover, if the transducer is located in
a scanhead or other imaging probe, the term "fixed" may also mean
that the transducer is not moved in an azimuthal or longitudinal
direction relative to the scan head, probe, or portions thereof
during operation. The transducers can be moved between the
acquisition of ultrasound frames; for example, the transducer can
be moved between scan planes after acquiring a frame of ultrasound
data, but such movement is not required for their operation. As one
skilled in the art would appreciate however, the transducer of the
present system can be moved relative to the object imaged while
still remaining fixed as to the operating parameters. For example,
the transducer can be moved relative to the subject during
operation to change position of the scan plane or to obtain
different views of the subject or its underlying anatomy.
[0062] Arrayed transducers have a number of elements. In one
embodiment, the transducer used to practice one or more aspects of
the present invention has at least 64 elements, e.g., 256 elements.
The transducer can also include fewer or more than 256 elements.
The transducer elements can be separated by a distance equal to
about one-half the wavelength to about two times the wavelength of
the center transmit frequency of the transducer (referred to herein
as the "element pitch."). In one aspect, the transducer elements
are separated by a distance equal to about the wavelength of the
center transmit frequency of the transducer. Optionally, the center
transmit frequency of the transducer used is equal to or greater
than 15 MHz. For example, the center transmit frequency can be
approximately 15 MHz, 20 MHz, 30 MHz, 40 MHz, 50 MHz, 55 MHz or
higher. In some exemplary aspects, the ultrasound transducer can
transmit ultrasound into the subject at a center frequency within
the range of about 15 MHz to about 80 MHz. In one embodiment
according to the present invention, the transducer has a center
operating frequency of at least 15 MHz and the transducer has an
element pitch equal to or less than 2.0 times the wavelength of
sound at the transducer's transmitted center frequency. The
transducer can also have an element pitch equal to or less than 1.5
times the wavelength of sound at the transducers transmitted center
frequency.
[0063] By non-limiting example, one transducer that may be used
with the described system can be an arrayed transducer as described
in U.S. Pat. No. 7,230,368, U.S. Publication No. 2007/0222339, and
U.S. Provisional Application No. 61/192,661, which are hereby
incorporated by reference. The transducer may also comprise an
array of piezoelectric elements that can be electronically steered
using variable pulsing and delay mechanisms. The processing system
according to various embodiments of the present invention may
include multiple transducer ports for the interface of one or more
transducers or scanheads. As previously described, a scanhead can
be hand held or mounted to rail system and the scanhead cable can
be flexible. Transducers are also commercially available from
VisualSonics, Inc.
Ultrasound Signal Acquisition
[0064] The system can further comprise one or more signal samplers
for each receive channel. The signal samplers can be
analog-to-digital converters (ADCs). The signal samplers can use
direct sampling techniques to sample the received signals.
Optionally, the signal samplers can use bandwidth sampling to
sample the received signals. In another aspect, the signal samplers
can use quadrature sampling to sample the received signals.
Optionally, with quadrature sampling, the signal samplers comprise
sampling clocks shifted 90 degrees out of phase. Also with
quadrature sampling the sampling clocks also have a receive period,
and the receive clock frequency can be approximately equal to the
center frequency of a received ultrasound signal but may be
different from the transmit frequency. For example, in many
situations, the center frequency of the received signal has been
shifted lower than the center frequency of the transmit signal due
to frequency dependent attenuation in the tissue being imaged. For
these situations the receive sample clock frequency can be lower
than the transmit frequency.
[0065] An acquired signal can be processed using an interpolation
filtration method. Using the interpolation filtration method a
delay resolution can be used, which can be less than the receive
clock period. In an exemplary aspect, the delay resolution can be,
for example, 1/16 of the receive clock period.
[0066] The processing unit can comprise a receive beamformer. The
receive beamformer can be implemented using, for example, at least
one field programmable gate array (FPGA) device. The processing
unit can also comprise a transmit beamformer. The transmit
beamformer can also be implemented using, for example, at least one
FPGA device.
[0067] In one aspect, 512 lines of ultrasound are generated,
transmitted into the subject and received from the subject for each
frame of the generated ultrasound image. In a further aspect, 256
lines of ultrasound can also be generated, transmitted into the
subject and received from the subject for each frame of the
generated ultrasound image. In another aspect, at least two lines
of ultrasound can be generated, transmitted into the subject and
received from the subject at each element of the array for each
frame of the generated ultrasound image. Optionally, one line of
ultrasound is generated, transmitted into the subject and received
from the subject at each element of the array for each frame of the
generated ultrasound image.
[0068] The ultrasound systems described herein can be used in
multiple imaging modes. For example, the systems can be used to
produce an image in B-mode, M-mode, Pulsed Wave (PW) Doppler mode,
power Doppler mode, color flow Doppler mode, RF-mode and 3-D mode.
The systems can be used in Color Flow Imaging modes, including
directional velocity color flow, Power Doppler imaging and Tissue
Doppler imaging. The systems can also be used with Steered PW
Doppler, with very high pulse repetition frequencies (PRF). The
systems can also be used in M-Mode, with simultaneous B-Mode, for
cardiology or other applications where such techniques are desired.
The system can optionally be used in Duplex and Triplex modes, in
which M-Mode and PW Doppler and/or Color Flow modes run
simultaneously with B-Mode in real-time. A 3-D mode in which B-Mode
or Color Flow mode information is acquired over a 3-dimensional
region and presented in a 3-D surface rendered display can also be
used. A line based image reconstruction or "EKV" mode, can be used
for cardiology or other applications, in which image information is
acquired over several cardiac cycles and recombined to provide a
very high frame rate display. Line based image reconstruction
methods are described in U.S. Pat. No. 7,052,460, which is hereby
incorporated by reference. Such line based imaging methods image
can be incorporated to produce an image when a high frame
acquisition rate is desirable, for example when imaging a rapidly
beating mouse heart. In the RF acquisition mode, raw RF data can be
acquired, displayed and made available for off-line analysis.
[0069] In one embodiment, the transducer can transmit at a pulse
repetition frequency (PRF) of at least 500 hertz (Hz). The system
can further comprise a processing unit for generating a color flow
Doppler ultrasound image from the received ultrasound. Optionally,
the PRF is between about 100 Hz to about 150 KHz. In M-Mode or RF
Mode the PRF is between about 100 Hz and about 10 KHz. For Doppler
modes, the PRF can be between about 500 Hz and about 150 KHz. For
M-Mode and RF mode, the PRF can be between about 50 Hz and about 10
KHz.
[0070] Exemplary specifications of the system may include those
specifications listed in Table 1, below:
TABLE-US-00001 TABLE 1 System Specifications Number of transducer
elements supported Up to 256 Transmit channels (active aperture) 64
Receive channels 64 Transducers supported Linear, curved linear
Center frequency range 15 to 55 MHz Data acquisition method
Quadrature sampling BF sampling frequency range 12 to 62 MHz
Receive BF fine delay implementation Interpolation filter Receive
delay resolution T/16 ADC number of bits 10 Transmit delay
resolution T/16 TGC yes Synthetic Aperture yes Maximum transmit
voltage 80 Vpp Transmit power control yes Multiple Transmit focal
zones yes Transmit cycle adjustment 1-32 B-mode frame rate max 200
CFI frame rate max 160 PW Doppler maximum PRF 150 KHz CFI maximum
PRF 75 KHz Doppler beam steering yes Cine buffer size 300 frames
Physiological signal acquisition yes Transducer connectors One or
more
Other Embodiments
[0071] Throughout this application, various publications are
referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference.
[0072] Unless otherwise expressly stated, it is in no way intended
that any method set forth herein be construed as requiring that its
steps be performed in a specific order. Accordingly, where a method
claim does not actually recite an order to be followed by its steps
or it is not otherwise specifically stated in the claims or
descriptions that the steps are to be limited to a specific order,
it is no way intended that an order be inferred, in any respect.
This holds for any possible non-express basis for interpretation,
including: matters of logic with respect to arrangement of steps or
operational flow; plain meaning derived from grammatical
organization or punctuation; and the number or type of embodiments
described in the specification.
[0073] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
embodiments of the invention will be apparent to those skilled in
the art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the invention being indicated by the following
claims.
[0074] Other embodiments are in the claims.
* * * * *