U.S. patent application number 10/538826 was filed with the patent office on 2006-03-16 for method for acquiring electromagnetic signals and contrast product therefor.
Invention is credited to Paul Canioni, Jean-Michel Franconi, Sylvain Miraux, Eric Thiaudiere.
Application Number | 20060058642 10/538826 |
Document ID | / |
Family ID | 32338772 |
Filed Date | 2006-03-16 |
United States Patent
Application |
20060058642 |
Kind Code |
A1 |
Franconi; Jean-Michel ; et
al. |
March 16, 2006 |
Method for acquiring electromagnetic signals and contrast product
therefor
Abstract
The invention concerns a system capable of generating a magnetic
indication B.sub.o comprising gradients (Gx, Gy, Gz) in certain
directions, transmitting ratio frequency wave pulse sequences (RF)
perpendicular to B.sub.o in a range of adjustable frequencies, and
detecting electromagnetic signals received from a body part (4).
The method consists in: injecting a contrast product in said body
part, capable of being temporarily fixed in an observed zone (1),
and comprising and element capable of causing chemical displacement
of a resonance frequency of water hydrogen protons; exciting said
body part, using a radio frequency wave pulse sequence: in a range
of frequencies adjusted on the basis of the magnetic induction
B.sub.o and the chemical displacement for some of said waves:
detecting the electromagnetic signals received in said body part,
substantially corresponding to the magnetic resonance signals of
the protons of the observed zone having undergone the chemical
displacement.
Inventors: |
Franconi; Jean-Michel;
(Merignac, FR) ; Miraux; Sylvain; (Merignac,
FR) ; Thiaudiere; Eric; (Bordeaux, FR) ;
Canioni; Paul; (Pessac, FR) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
32338772 |
Appl. No.: |
10/538826 |
Filed: |
December 8, 2003 |
PCT Filed: |
December 8, 2003 |
PCT NO: |
PCT/FR03/03628 |
371 Date: |
June 13, 2005 |
Current U.S.
Class: |
600/420 |
Current CPC
Class: |
G01R 33/485 20130101;
G01R 33/5601 20130101; A61K 49/18 20130101; A61B 5/055
20130101 |
Class at
Publication: |
600/420 |
International
Class: |
A61B 5/05 20060101
A61B005/05 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 13, 2002 |
FR |
0215826 |
Claims
1. A method for acquiring electromagnetic signals received from at
least one part of a body placed in a system comprising means for
generating a magnetic induction B.sub.0, said magnetic induction
comprising gradients in certain directions in space, means for
transmitting radio frequency wave pulse sequences perpendicular to
the magnetic induction B.sub.0 in a range of adjustable
frequencies, and means for detecting electromagnetic signals
received from said body part, the method comprising the following
steps: a) injecting, into said body part, an amount of contrast
product capable of being temporarily fixed in or of passing through
an observed zone of said body part, said contrast product
comprising at least one element capable of causing a chemical shift
of a resonance frequency of water hydrogen protons; b) exciting
said body part by means of a radio frequency wave pulse sequence in
a range of frequencies adjusted according to the magnetic induction
B.sub.0 and to the chemical shift for at least some of said radio
frequency waves; c) detecting, coherently with the excitation of
step b), electromagnetic signals received from said body part, said
signals corresponding substantially to magnetic resonance signals
of the protons of the observed zone having undergone the chemical
shift.
2. The method as claimed in claim 1, in which the element capable
of causing a chemical shift and included in the contrast product
comprises a lanthanide.
3. The method as claimed in claim 2, in which the lanthanide is
chosen from at least one of dysprosium, praseodymium and
europium.
4. The method as claimed in claim 1, in which the contrast product
also comprises a cage that incorporates the element capable of
causing a chemical shift, such as DOTA or DTPA.
5. The method as claimed in claim 1, also comprising a step
consisting in forming an image from the electromagnetic signals
received from said body part that are detected, according to a
spatial coding dependent on the gradients of said magnetic
induction.
6. The method as claimed in claim 1, in which said radio frequency
wave pulse sequence comprises a first series of wave pulses having
a frequency adjusted selectively according to the magnetic
induction B.sub.0, followed by a second series of wave pulses in a
range of relatively nonselective frequencies adjusted according to
the magnetic induction B.sub.0 and to the chemical shift.
7. The method as claimed in claim 1, in which said observed zone
comprises a group of blood vessels.
8. The method as claimed in claim 1, in which the contrast product
is injected with a targeting molecule capable of being fixed to at
least one target that is part of the observed zone.
9. The method as claimed in claim 8, in which the target is a group
of cells expressing a gene of said body part.
10. The method as claimed in claim 1, comprising an additional
step, at the end of step (a), consisting in irradiating said body
part with a spectrum of radiofrequencies and in detecting the
electromagnetic signal frequencies received, so as to deduce
therefrom a resonance frequency of the protons of the observed zone
having undergone the chemical shift.
11. The method as claimed in claim 10, in which the observed zone
comprises a tumor zone of said body part and in which an indication
of the concentration of contrast product fixed in or passing
through the tumor zone is deduced from the resonance frequency of
the protons of the observed zone having undergone the chemical
shift, this indication being a vascularization index for said tumor
zone.
12. A contrast product intended to be injected into at least one
part of a body for the purpose of acquiring electromagnetic signals
from said body part, the contrast product comprising at least one
element capable of causing a chemical shift of a resonance
frequency of water hydrogen protons.
13. The contrast product as claimed in claim 12, in which the
element capable of causing a chemical shit comprises a
lanthanide.
14. The contrast product as claimed in claim 13, in which the
lanthanide is chosen from at least one of dysprosium, praseodymium
and europium.
15. The contrast product as claimed in claim 12, also comprising a
cage that incorporates the element capable of causing a chemical
shift, such as DOTA or DTPA.
Description
[0001] The present invention relates to the acquisition of
electromagnetic signals. It relates more particularly to the
acquisition of such signals received from a body part, in
particular a human or animal body part, in response to an external
electromagnetic solicitation.
[0002] Various methods for acquiring signals are known, in
particular in the magnetic resonance imaging (MRI) field. These
methods have common characteristics.
[0003] They generally consist in subjecting the body in question to
a high-intensity magnetic induction B.sub.0, typically between 0.1
and 3 Tesla. The effect of this induction is to orient the magnetic
moments of the protons of the hydrogen contained in the water
molecules of the body in a direction close to the main direction of
the magnetic induction B.sub.0.
[0004] The body part imaged is then subjected to a radiofrequency
wave applied perpendicular to the magnetic induction B.sub.0 and
the frequency of which is typically adjusted to the Larmor
precession frequency of the hydrogen nucleus in the magnetic
induction B.sub.0 in question. This frequency is proportional to
the intensity of the magnetic induction B.sub.0 and has the
specificity of bringing into resonance the protons of the hydrogen
contained in the water molecules of the body. By way of example,
for an induction B.sub.0 of 1 Tesla, the corresponding Larmor
frequency is in the region of 42 MHz.
[0005] Immediately after the transmission of this radio frequency
wave, the magnetic moments that have been subjected to the wave
begin to oscillate around their equilibrium position and again take
up a position along their original direction, close to that of the
magnetic induction B.sub.0. This phenomenon is known as proton
relaxation.
[0006] During the relaxation, each water proton that has come into
resonance creates, as a result, a relatively weak electromagnetic
signal, called a magnetic resonance signal. This signal can then be
detected by means of an appropriate detection module.
[0007] Gradients of the magnetic induction B.sub.0 can be used in
various spatial directions, so as to have different induction
values between two points in space, each corresponding to an
elementary volume of the body in question.
[0008] The use of magnetic induction B.sub.0 gradients therefore
allows spatial localization of the signal. The step of coding the
space by means of the gradients is carried out between the proton
excitation and the magnetic resonance signal reception.
[0009] These basic principles give rise to different methods of
exploitation so as to allow the production of a selective image for
a chosen element of the body observed, for example a blood
vessel.
[0010] In a first method, referred to as "time of flight" method,
the radio frequency waves are transmitted repeatedly and regularly,
in a train of pulses. The repetition of these waves is adjusted so
as to be sufficiently frequent for the proton relaxation not to
have time to be entirely complete before transmission of the next
wave. This saturation phenomenon means that the magnetic resonance
signal is greatly reduced. It virtually makes it possible to
eliminate the signals transmitted by the immobile protons, i.e.
typically the protons that are part of tissues of the body in
question.
[0011] On the other hand, mobile protons that penetrate the zone in
question without having been subjected beforehand to a train of
pulses come into resonance and create a magnetic resonance
hypersignal that can be detected. The mobile protons are typically
the protons contained in the water of the circulating blood.
[0012] This time of flight method therefore makes it possible to
distinguish between the relaxed mobile protons and the saturated
immobile protons and thus makes it possible to isolate a selective
signal corresponding, for example, to a blood activity. This method
can in particular be applied in the field of angiography, since it
makes it possible to detect a signal originating from a blood
vessel in particular.
[0013] It is, however, limited to the analysis of blood vessels
that are short and have a high flow rate, since, if the opposite is
true, the protons contained in the blood circulating in these
vessels rapidly undergoes saturation, like the protons of the
surrounding tissues.
[0014] A second method, referred to as "phase contrast" method,
takes advantage of the relationship that exists between the phase
of the detected magnetic resonance signal and the rate of proton
displacement in the body in question, to allow detection of blood
vessels within the body. However, this method has drawbacks insofar
as a prior estimation of the rate of circulation in the vessels is
necessary. In addition, since the phase is a quantity expressed to
within 2.pi., an ambiguity remains regarding the effective rate
deduced from a magnetic resonance signal.
[0015] These first two methods are therefore based on
characteristics associated with a displacement, in particular of
blood in the body. They thus find an application in the angiography
field. On the other hand, they do not make it possible to detect a
particular static or virtually static element of the body. They
cannot therefore be used as a basis for the formation of an image
for a particular organ or for a particular cell type.
[0016] A third method has made a name for itself in the last few
years in the angiography field. It comprises a step consisting in
injecting a contrast product into a body. In general, the contrast
product used is gadolinium attached to a chelating agent such as
DOTA (or tetraazacyclododecane tetraacetate) or DTPA (or
diethylenetriamine pentaacetate). The chelating agent is a
molecular cage that surrounds the gadolinium and makes it possible
to limit its toxicity with respect to the body into which it is
injected. The effect of this product is to decrease the relaxation
time of the protons that are in proximity. Specifically, the
contrast product contains single unpaired electrons which have a
paramagnetic effect that acts on the water protons.
[0017] This increase in proton relaxation makes it possible to
limit the saturation in the zone where the injected product is
located. The resulting magnetic resonance signal is therefore
greatly increased. Conversely, the protons that are not in
immediate proximity to the gadolinium keep an unchanged relaxation
time and therefore generate a lower magnetic resonance signal.
[0018] Initially after injection, the contrast product moves in the
blood vessels without being absorbed by the surrounding tissues.
Detection of the magnetic resonance signals therefore makes it
possible to distinguish between the blood vessels and the
surrounding tissues and also to form an image revealing this
distinction.
[0019] However, this technique also has drawbacks. In particular,
paramagnetic gadolinium, in addition to its action on proton
relaxation time, creates magnetic induction microgradients that
result in local distortions of the magnetic induction to which the
body is subjected. The frequencies of the waves transmitted are
dispersed. This effect can result in the loss of certain signals.
When the magnetic resonance signals are used to form an image of a
zone of the body in question, said image will therefore be
difficult to interpret. This results in the spatial resolution of
the images obtained by this technique being limited: this method
does not allow complete suppression of the signals derived from
tissues lacking contrast product.
[0020] An object of the present invention is to provide a method
for acquiring magnetic resonance signals that limits the problems
encountered in the above techniques.
[0021] Another object of the invention is to enable acquisition of
the signals from a selected observed zone, independent of its type.
For example, the observed zone may contain substantially mobile or
substantially immobile protons. It may be a blood vessel or a
vascularized network, but also an organ, a group of cells, or the
like.
[0022] The invention thus proposes a method for acquiring
electromagnetic signals received from at least one part of a body
placed in a system comprising means for generating a magnetic
induction B.sub.0, said magnetic induction comprising gradients in
certain directions in space, means for transmitting radio frequency
wave pulse sequences perpendicular to the magnetic induction
B.sub.0 in a range of adjustable frequencies, and means for
detecting electromagnetic signals received from said body part. The
method comprises the following steps: [0023] a) injecting, into
said body part, an amount of contrast product capable of being
temporarily fixed in or of passing through an observed zone of said
body part, said contrast product comprising at least one element
capable of causing a chemical shift of a resonance frequency of
water hydrogen protons; [0024] b) exciting said body part by means
of a radio frequency wave pulse sequence in a range of frequencies
adjusted according to the magnetic induction B.sub.0 and to the
chemical shift for at least some of said radio frequency waves;
[0025] c) detecting, coherently with the excitation of step b),
electromagnetic signals received from said body part, said signals
corresponding substantially to magnetic resonance signals of the
protons of the observed zone having undergone the chemical
shift.
[0026] The chemical shift provided by the contrast product brings
about a shift in the resonance frequency of the hydrogen protons
contained in the water in proximity to the injected contrast
product. This shift in frequency makes it possible to obtain a
selective signal from the protons chemically shifted during a radio
frequency-based solicitation taking into account this shift. Such
selective signal can advantageously be used as a basis for forming
an image.
[0027] The observed zone envisioned here may be of various types,
for instance a blood vessel, a group of cells expressing a gene, a
tumor zone, or the like.
[0028] The invention also proposes a contrast product intended to
be injected into at least one part of a body for the purpose of
acquiring electromagnetic signals from said body part. This product
comprises at least one element capable of causing a chemical shift
of a resonance frequency of water hydrogen protons.
[0029] The element included in the contrast product may
advantageously be a lanthanide, for example dysprosium,
praseodymium and/or europium, optionally attached to a chelating
agent, or any other element capable of inducing a modification of
the resonance frequency.
[0030] Other particularities and advantages of the present
invention will emerge from the following description of nonlimiting
implementation examples, with reference to the attached drawing in
which the single FIGURE is a simplified representation of an
observed zone to which the invention is applied.
[0031] According to the invention, an amount of contrast product is
injected into a body 4, which may be, for example, a human or
animal body, but which may also be an inert body. The injection is
performed in such a way that the contrast product is fixed at least
temporarily in or passes through an observed zone 1. In the case of
a human body, for example, the contrast product may be injected
intravenously. The observed zone may then comprise a blood vessel 2
through which the contrast product passes, and also the tissues 3
that surround this vessel.
[0032] The various steps of the method described below must take
place rapidly after injection of the contrast product so that the
latter remains essentially contained in the zone for which it is
desired to recover a magnetic resonance signal, i.e., in the
example illustrated in the FIGURE, the vessel 2, but not the
tissues 3 that surround it.
[0033] The contrast product used according to the invention has the
property of effecting a chemical shift on the hydrogen protons that
are in proximity thereto. This is because such a product contains
atoms whose electron cloud is capable of modifying the local
magnetic induction experienced by the nucleus observed. The protons
that are in proximity to the contrast product, for example the
protons contained in the hydrogen of the water of the blood
circulating in the vessel 2, are subjected to this magnetic
induction.
[0034] If the protons in contact with the contrast product are
subjected to a magnetic induction B.sub.0, their resonance
frequency is no longer the Larmor frequency v.sub.0 proportional to
the amplitude of B.sub.0, but a frequency v.sub.1 that is shifted
with respect to v.sub.0. By way of illustration, if the chemical
shift created by the contact product is 3.5 parts per million
(ppm), the following frequency relationship is obtained:
v.sub.1-v.sub.0=3.5.times.10.sup.-6.times.v.sub.0. For a magnetic
induction B.sub.0=1.5 T, the Larmor frequency v.sub.0=63 MHz, and a
frequency shift v.sub.1-v.sub.0.apprxeq.220 Hz is therefore
obtained between the protons that are in proximity to or not in
proximity to the contrast product.
[0035] It should be noted that the chemical shift property is not
inherent to all products. In particular, gadolinium, commonly used
as a contrast agent for its properties of reducing the proton
relaxation time as explained in the introduction, causes virtually
no chemical shift. On the other hand, three other elements of the
lanthanide family are notable for their chemical shift action.
These are dysprosium (Dy), praseodymium (Pr) and europium (Eu).
[0036] For example, as regards dysprosium, the chemical shift
created .DELTA. (in ppm) is proportional to the concentration of
dysprosium (in millimoles per liter) with a proportionality
coefficient of 0.185, i.e. .DELTA.=0.185*[Dy].
[0037] Conventionally, cages are used to surround the lanthanides
in order to limit their toxicity, as was the case for gadolinium.
These cages are typically chelating agents such as DOTA or DTPA.
The contrast product used is therefore advantageously a lanthanide
chelate capable of generating a chemical shift, such as Dy-DOTA,
Dy-DTPA, Pr-DOTA or Pr-DTPA.
[0038] The body 4 is placed, immediately before or after injection
of the contrast product, in a system that surrounds a part of the
body and that is capable of generating a high-amplitude magnetic
induction B.sub.0. This induction comprises gradients in principle
directions in space according to the type of information that it is
desired to acquire. For example, if it is desired to obtain
magnetic resonance signals for elementary volumes in
three-dimensional space, it will be advisable to introduce coding
gradients G.sub.x, G.sub.y and G.sub.z for the magnetic induction
B.sub.0 in three main perpendicular directions (x, y, z) in space,
in a manner known in itself. By means of this technique, magnetic
induction values that are different between elementary volumes of
the body 4 are ensured.
[0039] The system in which the body 4 is placed also has a
transmitter of radio frequency wave pulse sequences in a range of
adjustable frequencies that may be more or less selective,
according to the duration of transmission of the corresponding
waves. These RF waves are transmitted perpendicular to the
direction of the magnetic induction B.sub.0. When a wave is
transmitted at a frequency corresponding to the proton resonance
frequency, said protons are then taken out of their equilibrium
position in a direction close to that of the induction B.sub.0, and
then they gradually return to this equilibrium position.
[0040] According to the invention, the protons in proximity to the
injected contrast product have a resonance frequency that is
shifted with respect to the usual Larmor frequency. Advantage is
then taken of this particularity in order to recover
electromagnetic signals only from these chemically shifted
protons.
[0041] For this, at least two methods can be envisioned. According
to a first embodiment, a radio frequency wave pulse sequence is
transmitted with a frequency adjusted selectively to the value of
the frequency shifted due to the chemical shift, i.e. v.sub.1
according to the notation employed above.
[0042] At the end of each transmission of a radio frequency wave
pulse sequence, a reception module detects and evaluates the
transmitted magnetic resonance signal. According to the principle
explained above, only the protons in the vessel 2 of the example
illustrated in the FIGURE come into resonance and generate a
magnetic resonance signal. The other protons that are not in
proximity to the injected contrast product, i.e. typically the
protons present in the tissues 3, generate virtually no signal.
[0043] Thus, if an image of the observed zone 1 is realized, for
example in a spatial plane, by taking advantage of the magnetic
induction gradients, and with each point of the image corresponding
substantially to a detected signal value, as a function of its
geographical position in the plane under consideration according to
a conventional spatial coding, the zones where the contrast product
has been fixed can be clearly distinguished. An image is thus
obtained, where the vessel 2 will be visible, while the tissues 3
will be invisible.
[0044] This embodiment is therefore entirely advantageous. However,
it has the drawback of requiring a sequence of radio frequency
transmissions that are selective with respect to frequency, which
means that a considerable transmission time is needed. When the
observed zone is large, the signal acquisition time may prove to be
disadvantageous.
[0045] A second advantageous embodiment makes it possible to limit
the magnetic resonance signal acquisition time. It consists in
using a radio frequency wave pulse transmission sequence comprising
a first series of selective wave pulses adjusted to a frequency
corresponding substantially to the Larmor frequency for the water
protons not chemically shifted, i.e. the protons of the tissues 3
in the example illustrated. These waves are transmitted with a
sufficient duration to saturate the protons concerned, to such an
extent that these protons no longer transmit any significant
magnetic resonance signal at the end of the first series of wave
pulses.
[0046] The radio frequency wave transmission sequence also
comprises a second series of wave pulses that are relatively
nonselective in terms of frequency, each wave of the sequence being
transmitted over a short period of time. The range of frequencies
covered by these waves comprises the resonance frequency of the
chemically shifted protons, i.e. of the protons of the vessel 2.
Thus, only the latter protons will come into resonance upon
transmission of the second series of waves, the protons of the
tissues 3 being saturated. This makes it possible to rapidly
receive the signals coming from only the protons of the vessel
2.
[0047] In this way, the signals transmitted by the chemically
shifted protons are isolated with precision. Furthermore, the
contrast products used with dysprosium, praseodymium or europium
have only a limited action on the distortion of the magnetic
induction in the observed zone, through the creation of magnetic
induction microgradients, unlike gadolinium. The images obtained by
applying this technique therefore potentially have a greater
spatial resolution than the known techniques using gadolinium
chelates.
[0048] As was described above, the chemical shift engendered by
injection of the contrast product, for example dysprosium, as a
function of the concentration of the latter, is known. This prior
knowledge can make it possible to precisely select the frequency of
the wave to be transmitted in the observed zone. However, in
another advantageous embodiment, it is possible to determine the
frequency resulting from the chemical shift without prior
knowledge. For this, the observed zone 1 of the body 4 is subjected
to successive waves in a broad spectrum of radiofrequencies and the
magnetic resonance signals generated by the observed zone in
reaction to each of these waves are detected. The main frequency
that causes the protons of the observed zone having undergone the
chemical shift to come into resonance is then deduced
therefrom.
[0049] So far, the observed zone 1, illustrated in the FIGURE, has
been taken to comprise a blood vessel 2 surrounded by tissues 3.
This representation makes it possible to envision applications of
the present invention in the angiography field.
[0050] However, the invention can also be applied to other types of
observed zones. In particular, the observed zone may comprise a
target, which may, for example, be a cell, a molecule, a protein,
or a group of targets of the body under consideration, such as a
group of cells expressing a gene.
[0051] In this situation, a known targeting molecule is
advantageously attached to the contrast product injected into the
body, such that the latter is temporarily fixed in the target. The
steps described above can then be carried out so as to acquire
magnetic resonance signals coming from the target only, with the
exclusion of certain surrounding tissues in which the contrast
product has not been fixed. This embodiment is particularly
advantageous and finds applications in the field of cellular and
molecular imaging, for example for studying gene expression in
vivo, for localizing a particularly biological activity, or the
like.
[0052] The observed zone may also be a zone of angiogenesis, for
example a tumor zone. Such a zone generally comprises a
vascularized network, the vascularization index of which gives an
indication regarding the malignant or benign nature of the
tumor.
[0053] In one embodiment, the invention makes it possible to
determine such a vascularization index. To this effect, the
lanthanide chelate used as contrast product is injected so as to be
temporarily fixed in the tumor zone. As described above, it is
possible to realize a spectrum in this observed zone, i.e. to
transmit successive radio frequency waves within a broad spectrum
of frequencies. The resonance frequency of the protons located in
the vascularized network present in the tumor zone is deduced
therefrom, this resonance frequency being substantially the
frequency for which magnetic resonance signals were received
(outside the conventional Larmor frequency of the water protons not
having experienced a chemical shift). Advantageously, this
operation can be carried out several times at successive moments so
as to make it possible to monitor any change in the time of this
resonance frequency.
[0054] As was indicated above, the chemical shift caused by the
contrast product, for example based on dysprosium, is proportional
to the concentration of dysprosium. Determination of the resonance
frequency in the tumor zone, which is itself proportional to the
chemical shift, then gives an indication of the concentration of
contrast product fixed in the observed zone. It is therefore
understood that this indication constitutes a vascularization index
that can be taken into account in a subsequent analysis of the
tumor.
[0055] As in the previous cases, the magnetic resonance signals
coming from the tumor zone can be acquired so as to characterize in
greater detail the vascularized network present in the tumor zone.
An image of the zone can also be obtained from this
acquisition.
* * * * *