 |
Description  |
|
|
BACKGROUND OF THE INVENTION
Technical Field
The application of nuclear magnetic resonance (NMR) to the study and
imaging of intact biological systems is relatively new. Like X-rays and
ultrasound procedures, NMR is a non-invasive analytical technique which
can be employed to examine lining tissues. Unlike X-rays, however, NMR is
a non-ionizing, non-destructive process that can be employed continuously
to a host. Further, NMR imaging is capable of providing anatomical
information comparable to that supplied by X-ray CAT scans in any
orientation without patient discomfort. On the other hand, the quality of
projections or images reconstructed from currently known NMR techniques
either rival or transcend those observed with ultrasound procedures. Thus
NMR has the potential to be one of the most versatile and useful
diagnosing tools ever used in biological and medical communities today.
NMR occurs when nuclei with magnetic moments are subjected to a magnetic
field. If electromagnetic radiation in the radio-frequency region of the
spectrum is subsequently applied, the magnetized nuclei emit a detectable
signal having a frequency similar to the one applied.
Many nuclei have intrinsic magnetism resulting from its angular momentum,
or spin, of such nuclei. Resembling a bar magnet, the spin property
generates a magnetic dipole, or magnetic moment, around such nuclei. Thus,
when two external fields are applied to an object the strong magnetic
field causes the dipoles for such nuclei, e.g., nuclei with spin
designated 1/1, to align either parallel or anti-parallel with said
magnetic field. Of the two orientations, the parallel alignment requires
the nuclei to store less energy and hence is the more stable or preferred
orientation. The second applied field comprises radio-frequency waves of a
precise frequency or quantum of electromagnetic radiation. These waves
cause such nuclei to nutate or flip into a less stable orientation. In an
attempt to re-establish the preferred parallel or stable orientation, the
excited nuclei will emit electromagnetic radio waves at a frequency
nominally proportional to the magnitude of the strong field, but
specifically characteristic of their chemical environment.
NMR technology therefore detects radio-frequency signals emitted from
nuclei as a result of a process undergone by the nuclei when exposed to at
least two externally applied fields. If a third magnetic field in the form
of a gradient is applied, nuclei with the same magnetogyric constant will
nutate at different frequencies, i.e., Larmor frequencies, depending upon
the location within the object. Thus, similar nuclei in an object can be
detected discriminately for a particular region in said object according
to their Larmor frequency corresponding to a particular magnetic field
strength along the applied magnetic gradient, as demonstrated by the
following equation
f.sub.o =.gamma.H.sub.o
wherein f.sub.o is the Larmor frequency, .gamma. is the magnetogyric
constant, and H.sub.o is the applied magnetic field.
Several factors, however, limit the usefulness of NMR applications in vivo.
In general, NMR is an insensitive radiologic modality requiring
significant amounts of nuclei with magnetic moments to be present in an
object. Consequently, not all nuclei in vivo are present in sufficient
quantities to be detected by present NMR techniques. Further, not all
nuclei found in vivo have magnetic moments. Some of the more common
isotopes that do not have magnetic moments which are found in vivo include
.sup.12 C, .sup.16 O and .sup.32 S.
Thus, current NMR applications in vivo are restricted to those nuclei that
have magnetic moments and are sufficiently abundant to overcome the
insensitivity of present NMR techniques. For the most part, in vivo NMR
applications almost invariably concern themselves with imaging or
detecting the water distribution within a region of interest derived from
the detection of proton resonance. Other nuclei not only have lower
intrinsic NMR sensitivities but are also less abundant in biological
material. Consideration has been given, however, to the use of other
nuclei such as .sup.31 P which represents the next best choice for NMR in
vivo applications to its natural and abundant occurrence in biological
fluids. For example, .sup.31 P NMR has been found to provide an indirect
means for determining intracellular pH and Mg.sup.++ concentration simply
by measuring the chemical shift of the inorganic phosphate resonance in
vivo and determining from a standard titration curve the pH or Mg.sup.++
concentration to which the chemical shift corresponds. (Gadian, D. G.,
Nuclear Magnetic Resonance and its Applications to Living Systems, First
Ed. Oxford Clarendon Press, pp. 23-42 (1982); Moon, R. B. and Richards, J.
H., Determination of Intracellular pH by 31.sub.P Magnetic Resonance. J.
Biological Chemistry 218(20;7276-7278 (Oct. 25, 1973)). In addition,
23.sub.Na has been used to image a heart perfused with a medium containing
145 mM sodium in vivo. Difficulties with these nuclei arise because of
inherent sensitivity losses due to the lower resonant frequencies of these
nuclei (Moon, R. B. and Richards, J. H., Determination of Intracellular pH
by .sup.31 P Magnetic Resonance, J. Biol. Chem. 218(20):7276-7278 (Oct.
25, 1973).
Another stable element which is uniquely suited for NMR imaging is F
because its intrinsic sensitivity practically commensurates with that of
protons, it has a spin of 1/2 so as to give relatively uncomplicated, well
resolved spectra, its natural isotopic abundance is 100 percent, it gives
large chemical shifts, and its magnetogyric constant is similar to that of
protons. Accordingly, the same equipment used for proton NMR can be used
in vivo. However, F NMR applications are not used due to practical
non-existence in biological materials of fluorine observable by NMR
methods normally employed in studying biological systems. However, nuclear
medicine procedures using a 18.sub.F positron emitter are well documented
and include, for example, bone scanning, brain metabolism and infarct
investigations using fluorodeoxyglucose, and myocardial blood flow and
metabolism. Suggestions have been presented involving the study of
vascular system disorders with F imaging (Holland, G. N. et al, .sup.19 F
Magnetic Reson. Imaging, J. Magnetic Resonance 28:133-136 (1977)) and the
localization/kinetics of fluorocarbon following liquid breathing. Further,
in vitro canine studies investigating the feasibility of fluorine as an
agent for NMR imaging of myocardial infarction have also been performed
(Thomas, S. R. et al, Nuclear Magnetic Resonance Imaging Techniques
Developed Modestly Within a University Medical Center Environment: What
Can the Small System Contribute at this Point?, Magnetic Resonance Imaging
1(1):11-21 (1981)).
Studies directed to conformational equilibria and equilibration by NMR
spectroscopy have been conducted, particularly with cyclohexane and
fluorocyclohexane rings. In such applications, the position of the
equilibria between conformational isomers and measurements of rates of
equilibration of such isomers as a function of temperature have been
determined. The studies, however, were dependent upon the implementation
of known temperatures to determine the equilibria and equilibrium rates
(Roberts, J. D., Studies of Conformational Equilibria and Equilibration by
Nuclear Magnetic Resonance Spectroscopy, Chem. in Britain. 2:529-535
(1966); Homer, J. and Thomas, L. F.: Nuclear Magnetic Resonance Spectra of
Cyclic Fluorocarbons. Trans. Faraday Soc. 59:2431-2443 (1963)). It has
further been illustrated that 13.sub.C may be employed as a kinetic
thermometer in a laboratory environment. This particular application
requires the examination system to contain at least two chemically
exchanging sites which correspond to one exchange process and an
independent means of determining the kinetic parameters describing the
exchange process in order for 13.sub.C to serve as a kinetic thermometer.
Such application, however, is limited to determining temperature at
coalescence and is, thus, operable at only one temperature for each
independent exchange process as opposed to over a continuous range. The
method is further employed as a calibration technique and its accuracy is
inherently unreliable to be of practical significance (Sternhell, S.
Kinetic .sup.13 C NMR Thermometer, Texas A&M U. NMR Newsletter. 285:21-23
(June 1982)). Unfortunately, NMR studies based on .sup.13 F or .sup.13 C
require infusion in the body of molecules containing these atoms due to
their very low abundance in vivo.
Temperature has been measured by means of the NMR spectrum of liquid
samples for the purpose of calibrating the temperature control apparatus
of an NMR spectrometer. Many features of the NMR spectrum, for instance
chemical shifts, often show weak temperature dependence, and could be used
to determine temperature (Bornais, Jr. and Browstein, S., A
Low-Temperature Thermometer for .sup.1 H, .sup.19 F and .sup.13 C, J.
Magnet. Reson. 29:207-211 (1978)). The peak separation and spin-spin
coupling in the proton NMR spectrum of a liquid test sample changed by
1.75 Hz and 0.07 Hz, respectively, when the temperature was varied by
10.5.degree. C. In objects, such as animals, were the best obtainable
spectral resolution could be 10 to 50 Hz or larger, and it is desired to
measure temperatures to an accuracy of 1.degree. C. or 2.degree. C. or
better, such as means of temperature measurement is inapplicable.
As to temperature in an animal, it is well known that abnormal fluctuations
in temperature such as increases may reflect infection or hyperthermia,
while decreases may represent ischemia or hypothermia. Thus, it is useful
to measure temperature in an animal accurately, inexpensively and
reliably. Furthermore, induced hyperthermia can also be used as an
adjunctive cancer treatment.
In the past, temperature measurements have generally consisted of invasive
and cumbersome techniques that often result in less than reliable
measurements. Examples of such techniques comprise invading needles,
electrical wires, cables, or instruments that must be inserted into a
region of interest. Such penetrating procedures possess unfortunately the
potential to cause chemical and biological contamination to the host.
Thus, proper preparation and sterilization procedures are required to
prevent transmittal and corrosive contamination when the instruments to
detect temperature are reused. Another disadvantage inherent to the
conventional techniques concerns the discomfort and inconvenience
experienced from communication with penetrating probes. As to highly
delicate structures, the temperature may be obtained but not without
sacrifice to the integrity of the structure. Generally, the structure may
be damaged, repositioned or its dimensions changed. Short circuiting of
the employed instruments may add additional expenses and time to the
procedure. The instrument itself when exposed to physical and chemical
extremes may interfere with its reliability. Moreover, conventional
techniques are unable to measure a continuous temperature field in an
object or animal and, thus, the invasive and cumbersome procedure must be
duplicated for each time or at each point in space a temperature
measurement is desired, or employ simultaneously a large number of
temperature sensors.
Non-invasive and non-destructive temperature imaging in biological systems
may be useful in many disciplines. One important application is clinical
hyperthermia (HT) which is being used as an adjunctive cancer treatment
(Hahn, G. M., infra) Although very promising results have been obtained,
the effectiveness and safety of deep-seated HT treatment has been limited,
mainly due to a lack of temperature control (Gibbs, F. A., Hyperthermia
Oncology, eds. Taylor and Frances, Phila, pp 2155-167 (1984)). Indeed, the
effectiveness of a HT treatment depends upon the minimum temperature
reached in the tumor (greater than 42.degree. C.) while safety
considerations limit the maximum temperature that can be reached in normal
healthy tissues (less than 42.degree. C.) (Hahn, G. M., Hyperthermia in
Cancer, Planum Press (New York, 1982)). The temperature must be,
therefore, monitored throughout the entire heated region with at least one
cm spacial resolution and 1.degree. C. sensitivity (Hahn, G. M., supra).
A method to conduct non-invasive temperature monitoring by magnetic
resonance imaging (MRI) was recently proposed which employs Tl temperature
dependency (Parker D. L., Smith, V., Shelton, P., Med. Phys. 10:321
(1983); Dickinson, R. J., Hall, A. S., Hinde, A. J., Young, I. R., J.
Comput. Assist. Tomogr. 10:468 (1986); U.S. Pat. No. 4,558,279 to Ackerman
et al). MRI, a non-invasive and non-ionizing imaging method (Lauterbur, P.
C. (1975) Nature 18,69-83) has the advantage of producing anatomical
images of any part of the body in any orientation with high resolution.
Contrast in MRI is defined by parameters mainly related to certain
physical properties of water molecules. Temperature sensitivity of one of
these parameters, namely, the spin-lattice relaxation time or Tl has been
demonstrated in-vitro for different biological systems thereby suggesting
the thermal imaging potentiality of MRI (Lewa, C. J., Majeska, Z., Bull.
Cancer (Paris) 67:525-530 (1980) Parker, D. L., supra; Dickinson, R. J.,
supra). However, in general, precise Tl MRI measurements are difficult and
the accuracy for temperature determination is limited. In most cases the
accuracy is no greater than 2.degree. C./cm/5 min acquisition time.
(Parker D. L., Smith V. and Shelton P., supra; Dickinson R. J., Hall A.
S., Hinde A. J., and Young I. R., supra; U.S. Pat. No. 4,558,279).
Unfortunately, there are large variations in Tl between different tissues
and for the same tissue between different subjects. This has been ascribed
to the multifactorial nature of Tl (Bottomley, P. A., Foster, T. H.,
Argensinger, R. E., Pfeifer, L. M., Med. Phys II: 425-448 (1984). The
applicability of this technique seems therefore to be limited because a
relative change of at least 1% in Rl is needed to detect a 1.degree. C.
change in temperature (Cetas, E. C., supra) and T.sub.1 measurements using
MRI are difficult due to its sensitivity to environment (Young, I. R.,
Bryant, D. J. and Payne, J. A. Magn Res. Med. 2:355-389 (1985). U.S. Pat.
Nos. 4,319,190, 4,558,279 and 4,361,807 also disclose methods of imaging
chemical shifts in a body. However, these methods were not directly
applied to the indirect measurement of temperatures in vivo. The use of
chemical-shift resolved MRI has also been experimentally proposed but has
severe limitations (Hall, L. D., Reson. 65:501-505 (1983)). Furthermore,
all these techniques have failed for temperature monitoring in vivo, so
that NMR was not considered as a likely temperature imaging method.
A variety of methods are available in the prior art for measuring the
diffusion constant of the regents of a medium. One is that described by
George et al "Translation on Molecular Self-Diffusion in Magnetic
Resonance Imaging: Effects and Applications", in Biomedical Magnetic
Resonance, published by Radiology Research and Education Foundation, San
Francisco 1984. This method describes the measurement of the diffusion
constant by comparing the relative effect of the diffusion of the studied
medium and on a standard substance during different magnetic excitation
sequences. This method relies on increasing the intensity of a section
selection gradient which modifies the thickness of the studied section.
Thus, this method can only be applied to objects which are finer than the
finest section thickness obtained by sequences used and practically of not
use in animal or human subjects. The sensitivity of this method to
diffusion is also relatively limited.
Another method which lends itself to the measurement of temperatures in
living tissues, including animals and humans utilizes relatively long echo
times and effective gradients as a result of their intensity and position.
In addition the exact determination of diffusion coefficients is obtained
without a standard substance by basing the calculations on acquisition
parameters. This method is described in a patent application entitled
"Process for Imaging by Nuclear Magnetic Resonance" filed by Breton, E.
A., LeBihan, D. and LeRoux, P. in France on June 27, 1985 (FR 85 09824)
and in the U.S. on Dec. 24, 1986 under a Ser. No. 06/946,034, now U.S.
Pat. No. 4,780,674, which is a Continuation-in-Part of U.S. application
Ser. No. 823,522 filed Jan. 29, 1986, now abandoned the entire contents of
which are incorporated herein by reference, with particular emphasis on
the characteristics and steps of the method such as the utilization of
basic sequences using Spin-Echoes to measure and image diffusion and
longer and/or more powerful field gradient pulses to eliminate the effects
of blood microcirculation.
An additional method is described in French patent application No. 86 13483
entitled "Method of Imaging by Nuclear Magnetic Resonance" by Breton, E.
A., and LeBihan, D. on Sept. 26, 1986. This application was also later
filed in the EPO on Sept. 21, 1987, in Japan on Sept. 25, 1987 and in the
U.S. with a Ser. No. 07/100,261 on Sept. 23, 1987, now U.S. Pat. No.
4,809,701. These patent applications describe improvements in diffusion
measurements and images which can be obtained when NMR excitation
sequences and recording of NMR signals by synchronization with heart beats
in living tissues. Diffusion measurements and images can be obtained
quickly by using Steady-State Free Precession NMR. Yet another method is
described in a patent application entitled "Precede and Imagerie des
Movements Intravoxels par RMN dans in corps" filed in France by LeBihan,
D. on Oct. 13, 1987 and has a Ser. No. 87 14098. This patent application
contains an invention which is related to the publication LeBihan, D.,
"Intravoxel Incoherent Motion Imaging Using Steady-State Free Presession",
Magnetic Resonance in Medicine 7:346 (1988). This is a method for the fast
imaging of diffusion by using Steady State Free Precision NMR. The entire
contents of the patent application and the above article are also
incorporated herein by reference.
In view of the foregoing description of the limitations posed by prior art
NMR temperature measuring techniques there is a clear need in the art,
with particularly imminent application to cancer treatments for an
improved method of determining in vivo the temperature coefficient and
obtaining temperature images which is safe, non-invasive and can provide
the sensitivity and reliability required of such measurements.
SUMMARY OF THE INVENTION
This invention relates to a novel and improved method of determining and
imaging the temperature or the temperature change of an object (human,
animal, liquid or solid) by nuclear magnetic resonance of molecular
diffusion coefficients, said method comprising
(a) placing the object in a magnetic field Bo at a temperature To;
(b) subjecting the thus positioned object to a first series of magnetic
resonance imaging sequences able to give first numerical values or images
of molecular diffusion coefficients, namely Do for individual points of
the object or of a limited volume thereof;
(c) maintaining the object or a part thereof utilized in step (b) to a
temperature T, or waiting for a spontaneous change to a temperature T in
said part;
(d) subjecting the thus positioned object to a second series of magnetic
resonance imaging sequences to obtain second numerical values or images of
molecular diffusion coefficients, namely D, for individual points of the
object or of a limited volume thereof;
(e) comparing point-by-point the values of the diffusion coefficients Do
allocated for the first series of diffusion images obtained in step (b)
with the values of the diffusion coefficients D obtained in the second
series of diffusion images in step (d) in order to determine and to
generate a third series of images representing temperature changes dT
between steps (b) and (d) for individual point i of the object or of a
limited volume of the object from the formula
dT.sub.i =(kTo/E) Log (D/Do).sub.i
wherein k is Boltzman's constant (1.38 10.sup.-23 J/K) and E is the
activation energy (.apprxeq.0.2 eV at 20.degree. C.), provided dT <<To and
E.apprxeq.constant,
(f) repeating steps (c) to (e) continuously for different points of the
object so that temperature changes dT.sub.i can be monitored continuously,
(g) determining the absolute temperature To for individual points of the
entire object or of a limited volume thereof so that by repeating steps
(b) to (f) the absolute temperature T can be determined and imaged
continuously in each point of the object or of a limited volume of the
object from the formula
T=To+dT.sub.i
wherein Dt is determined and imaged in step (e).
The present method may be utilized to determine the temperature of a
subject also receiving, e.g., cancer therapy, or other treatments where
the temperature of the body or of a particular portion of the body is
bound to be varied. The method of this invention is highly sensitive to
changes in temperature, accurate, non-invasive and provides a sensitivity
for the measurement of temperature which is greater than 2% in the
resolution of the temperature images better than 0.5.degree. C.
A more complete appreciation of the invention and many of the attendant
advantages thereof will be readily perceived as the same becomes better
understood by reference to the following detailed description when
considered in connection with the accompanying figure.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the relative variation of the diffusion coefficient as a
function of temperature change. T.sub.o is 36.7.degree. C. and D.sub.o is
2.31.times.10.sup.-3 mm.sup.2 /s.
FIG. 2 shows a schematic representation of the method of the invention.
Letters a through g correspond to respective steps (a) through (g) in the
claims.
Other objects, advantages and features of the present invention will become
apparent to those skilled in the art from the following discussion.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention arose from a desire to improve on prior methods for
the determination of body temperature, particularly associated with
hyperthermia (HT) which is used as an adjunctive cancer treatment. In
general, the effectiveness of HT treatments depend upon reaching a minimum
temperature in a tumor, e.g., mostly greater than 42.degree. C., while for
all practical purposes temperatures greater than 42.degree. C. are not
really permissable in normal healthy tissues. Therefore, the temperatures
applied during treatment must be thoroughly and accurately monitored
throughout the application of a treatment in the heated areas of the body
within at least 1 cm spacial resolution and 1.degree. C. sensitivity. This
degree of sensitivity and accuracy has not been attained by prior
non-invasive methods currently available.
The inventors discovered that by using molecular diffusion measurable by
nuclear magnetic resonance (NMR) techniques they could measure an image
body temperature. A relationship between the diffusion coefficients and
temperature known in the art is utilized as applied to the measurement of
body temperature. In addition, this invention also incorporates available
methods for quantitative diffusion imaging using MRI (LeBihan D., Breton
E., Lallemand D, Grenier P., Cabanis E. and Laval-Jeantet M., supra;
Taylor D. G. and Bushell M. C., Phys. Med. Biol. 30:345 (1985)); LeBihan,
D., Breton, E. (1985) C. R. Acad. Sc, supra; LeBihan, D., Breton, E.,
Lallemand, D., Grenier, P., Cabanis, E., Laval Jeantet, M., Radiology
1986, supra; LeBihan, D., Magn, Reson. Med., 1988, supra; Taylor, D. G.,
Bushell, M. C. (1985) Phys. Med. Biol. 30,345-349; Merkolt, K. D.,
Manicke, W., Frahm, J., J. Magn. Reson (1985).
The present method is based on the following theoretical considerations.
The following temperature dependence of the translational self-diffusion
coefficient D and viscosity are established on the basis of the
Stokes-Einstein relationship (Simpson, J. H. and Carr H. Y., Phys. Rev.
111:1401 (1958)).
D .alpha..about.exp (-E/kT) (1)
wherein k is Boltzman's constant (1.38 .sup.10 23 J/.degree.K.beta. and E
is the activation energy No. 2 eV at 20.degree. C., Simpson et al, supra).
Thus, it can be stated that when an object is subjected to changing
temperatures, these temperature changes induce changes in the diffusion
coefficient which can be calculated from differentiating the equation (1)
above as long as the variations of E with T are small, as follows.
dD/.sub.D =(E/kT)dT/T (2)
As can be seen from equation (2) above temperature changes may be detected
from diffusion coefficient measurements. This permits the application of
magnetic resonance technology of the measurement of diffusion coefficients
to the temperature of the object subjected to the magnetic field.
A map of temperature changes (T-T.sub.o).sub.xy can thus be obtained by the
method of the invention from two diffusion images D.sub.x,y and D.sub.o
x,y. The first image is obtained before heating (T.sub.o, D.sub.o) and the
second is obtained during heating at a temperature T (T, D). The two sets
of data can be correlated as follows.
(T-To).sub.x,y =(kT.sub.o.sup.2 /E) Log (D/D.sub.o).sub.xy (3)
provided that T-To<To in that E.apprxeq..about.constant.
Diffusion coefficients of hydrogen nuclei in water can be measured and
imaged using MRI for instance, (LeBihan, D., Breton, E., C. R. Acad,
supra; (LeBihan, D., Breton, E., C. R. Acad. Sc (Paris) 301, 1109-1112
(1985) LeBihan, D. Breton, E. Lallemand, D., Cabanis, E., Laval-Jeantet
supra)) The effect of molecular diffusion in the presence of a magnetic
field gradient on MR spin-echo signals was described long ago (Hahn, E.
L., Phys. Rev. 80:580 (1950). Diffusion produces a pure amplitude
attenuation of the MR signal due to the loss of phase coherence between
processing spins produced by their random walk through the gradient. This
amplitude attenuation A depends only on the diffusion coefficient D and
the gradient so that
A=exp (-b.multidot.D) (4)
where b is a gradient factor which can be calculated from gradient
characteristics (strength and duration) (LeBihan, D., Breton, E. A., C. R.
Acad-Sc, (1985) supra; LeBihan, D. Breton, E., Lallamond, D., Grenier, P.,
Cabanis, E., Laval-Jeantet, M., supra; Hahn, E. L., supra; Carr, Y. Y. and
Purcell E. M. supra; Stejskal, E. Tanner J. E., J. Chem. Phys 42:288
(1965)).
Stejskal and Tanner, supra, introduced a diffusion measurement method that
used pulsed magnetic field gradients, thereby improving the sensitivity of
the measurements and allowing smaller values of diffusion coefficients to
be determined. More recently, these concepts were extended to MRI
(LeBihan, D., Breton, E., Lallemand, D., Grenier, P., Cabanis, E. and
Laval-Jeantet, M. supra) and applied to a diffusion mapping method based
on two MR images differently sensitized to diffusion by the presence of
specially designed gradient pulses (LeBihan, D., Breton, E., Lallemand,
D., Grenier, P., Cabanis, E and Laval-Jeantet, M, supra; LeBihan, A. and
Breton, E. Under these conditions, the diffusion image is derived from
D.sub.x,y =Log(A.sub.2x,y /A.sub.1x,y)/(b.sub.1 -b.sub.2) (5)
where b.sub.1 and b.sub.2 are the calculated factors in both images, and
A.sub.2 /A.sub.1 is the amplitude attenuation ratio equal to the signal
amplitude ratio of both images because both images are identical with
respect to all the other MRI parameters.
The method of the invention has been tested at different temperatures which
are permissive to the human body. One such test is provided in the example
herebelow. These tests demonstrate the ability of MRI to measure
temperature changes using molecular diffusion imaging.
The sensitivity of the present method for temperature determination using
diffusion is at least twice that of available prior art procedures using
Tl (Parker, D. L., Smith, V., Shelton, P.; supra; Dickinson, R. J., Hall,
A. S., Hind, A. J., Young, I. R., supra: Bottomley, P. S., Forster, T. H.
Argersinger, R. E. and Pfeifer, supra; U.S. Pat. No. 4,558,279.
This increased sensitivity may be ascribed to the basis relationship
between diffusion, Tl, and temperature. Tl relaxation depends in part on
diffusional processes. However, in biological tissues, the diffusion term
that predominates in Tl is rotational diffusion which is 1.5 times less
sensitive to temperature than translation diffusion (Abrogam, A.,
Principle Nuclear Magnetism (Oxford U. Press., London) (1961).
Furthermore, there are other contributions to Tl so that its temperature
dependance may not be simple (Abrogam, E. O., supra).
In addition, Tl determinations using MRI are often inaccurate because of
difficulties in obtaining homogeneous MR radiofrequency fields through the
imaged slice (Young, I. R., Bryant, D. J. and Payne, J. A., Magn. Reson.
Med. 2:355-389 (1985). These difficulties disappear when using the present
diffusion imaging method because it uses two MR imaging sequences
identical as far as the radiofrequency field is concerned LeBihan, D.,
Breton, E, (1985) supra; (LeBihan, D., Breton, E., Lallemand, D., Grenier,
P. Cabanis, E. and Laval-Jeantet, M. supra; LeBihan, D. and Breton, E.,
supra) Under these conditions, the signal imperfections will cancel each
other.
This method can be applied in-vitro and in-vivo for instance during
clinical hyperthermia treatments. Moreover, the relationship of equation
(3) between T and D applies to biological tissues as well as the material
of the sample in biological tissues. Measured diffusion coefficients can
be affected by restricted diffusion phenomena related to compartmental
effects on water mobility (Stejskal, E. D., J. Chem Phys. 43:3597 (1965).
Moreover, the non-Brownian character of restricted diffusion may affect
its relation with temperature. However, restricted diffusion effects are
limited if necessary by shortening the diffusion measurement times (echo
time TE).
Furthermore, the use of Eq.(3) for temperature measurement assumes the
previous determination of the activation energy E in biological tissues,
that there is a smaller variation in E between the same tissue in
different subjects, and that there are substantially no hysteresis effects
when the temperature increases up to 42.degree. C. and then decreases back
to 37.degree. C. contrary to what was found for the temperature dependance
of Tl (Lewa, C. J., Majeska, Z., Bull Cancer (Paris) 67:515-530 (1980)).
In vivo diffusion coefficients should be measured with extreme care. These
measurements may be affected by other intravoxel incoherent motions of
water present in biological tissues as well known in the art (LeBihan, D.,
Breton, E., Lallemand, D., Grenier, P, Cabanis, E. and Laval-Jeantet, M.,
supra). In particular, the separation of the contributions of diffusion
from that of blood microcirculation must be achieved using a known
appropriate algorithm (LeBihan, D., Breton, E., Lallemand, D., Aubin, M.
L., Vignaud, J. and Laval-Jeantet, M., Radiology 186:497 (1988). On the
other hand perfusion imaging may be very useful in hyperthermia studies,
blood circulation having an important role in thermal clearance (Hahn, G.
M., Physics and Technology of Hyperthermia pp. 441-447, Martinus Nijhoff
Publishers, Boston). However, other NMR methods able to generate diffusion
images can be used for temperature imaging, for instance, methods using
stimulated echoes (Merboldt, K. D., Manicke, W., Maase, A. J., Magn. Reson
64:81 (1985) or methods using Steady-State Free Precession (LeBihan, D.)
Magnetic Resonance in Medicine 7, 346-351, 1988).
More specifically, the method of the invention is a method of determining
and imaging the temperature or the temperature change of an object (human,
animal, liquid or solid) by nuclear magnetic resonance of molecular
diffusion coefficients which comprises
(a) placing the object in a magnetic field Bo at a temperature To;
(b) subjecting the thus positioned object to a first series of magnetic
resonance imaging sequences to obtain first numerical values or images of
molecular diffusion coefficients D.sub.o.sup.i for various points of the
object or of a limited volume thereof;
(c) maintaining the object or part of the object including the points
measured in step (b) at a temperature or waiting for a spontaneous change
to said temperature T in said part of the object;
(d) subjecting the thus positioned object to a second series of magnetic
resonance imaging sequences to obtain values or images of molecular
diffusion coefficients D.sup.i for the same points of the object or of a
limited volume thereof measured in step (b);
(e) comparing point-by-point the values of the diffusion coefficients Do
allocated for the first series measured in step (b) with the values of the
diffusion coefficients D.sup.i obtained in the second series obtained in
step (d) in order to determine and to generate a third series of images
representing temperature changes dT.sub.i between steps (b) and (d) for
each point of the object or of a limited volume of the object measured in
steps (b) and (d) from the formula
dT.sub.i =(kTo.sup.2 /E) Log (D/Do).sub.i
wherein k is Boltzman's constant (1.38 10.sup.-23 J/K) and E is the
activation energy (.apprxeq.0.2 eV at 20.degree. C.), provided dT<<To and
E.apprxeq.constant;
(f) repeating steps (c) to (e) continuously so that temperature changes
dT.sub.i can be monitored continuously;
(g) determining the absolute temperature T.sup.i o for each measured point
of the object or of a limited volume of the object so that by repeating
steps (b) to (f) the absolute temperature T.sup.i can be determined and
volume thereof from the formula
T.sup.i =T.sup.i o+dT.sub.i
where dT is determined and imaged in step (e).
In a particularly useful embodiment of the method of the invention the
magnetic field utilized is a constant magnetic field. Particularly
suitable values for the magnetic field are about 0.2 T to 10 T and more
preferably, 0.1 T to 2 T. However, other values may also be utilized.
Suitable temperatures T.sub.o to which the subject/object is exposed when
practicing the present invention are (for water) from 0 to 100.degree. C.,
and more preferably 25 to 45.degree. C. The measurements can be attained
at ambient temperature as well.
In yet another particularly embodiment of the method, the series of
magnetic resonance imaging sequences used to obtain measurements and
images of molecular diffusion can be Spin-Echo sequences, Stimulated Echo
sequences or Steady-State Free Precession sequences using
gradient-recalled echoes.
The method using Spin-Echoes is described in U.S. application Ser. No.
946,034 filed on Dec. 24, 1986 and in LeBihan D. and Breton E., supra;
LeBihan D., Breton, E., Lallemand D., Grenier P., Cabanis E., now U.S.
Pat. No. 4,780,674 Laval-Jeantet M., supra the entire contents of which
are incorporated herein by reference.
The method using Stimulated Echoes is described in Merboldt, K. D., Manicke
W., Frahm J., J. Magn. Reson. 64:479-486 (1985), the entire contents of
which is incorporated herein by reference.
The method using Steady-State Free Precession is described in French
application Ser. No. 8714098 filed on Oct. 13, 1987, and in LeBihan, D.,
Magn. Reson. Med., 7:346 (1988) the entire contents of which are also
incorporated herein by reference.
In a particular embodiment of the method of the invention, the calculation
of the diffusion coefficients D and Do from Nuclear Magnetic Resonance
sequences, as described for in the Spin-Echo method, the Stimulated Echo
method and the Steady-State Free Precession method, can also be progr | | |
