The present invention relates to nuclear magnetic resonance
(NMR) spectroscopy, as applied in radiological diagnostics under the name of in
vivo magnetic resonance spectroscopy (MRS) for the assessment of metabolic compounds
in the human body. More particularly, the present invention relates to modifications
of magnetic resonance experiments and also to an apparatus for execution of these
experiments, to transfer polarization between nuclei with the aim to enhance the
detection sensitivity of compounds by magnetic resonance or to enable spectral editing
of molecular fragments based on their coupling to specific isotopes.
Magnetic resonance spectroscopy (MRS) like magnetic resonance
imaging (MRI) is based on the nuclear magnetic resonance effect which was found
in the year 1946 and in the very beginning used for examination of the magnetic
characteristics of nuclei. Later it was found that the resonance signal of a nuclei
is also influenced by its chemical surrounding and that this so-called chemical
shift can be used to characterise chemical substances. This kind of examination
was established as the so-called "high resolution NMR" in vitro. This high resolution
NMR finds its application in the physical, chemical, biochemical and pharmaceutical
research and development in order to analyse the structure of complex macro molecules.
In the late seventies of the last century it was newly
discovered that the nuclear resonance signal can be used for non-invasive imaging
of living species, which is representing one of the most important radiological
examination methods in medicine until today.
However, it was not ignored that magnetic resonance imaging
further contains chemical information, which can be used to analyse biochemical
reactions, respectively metabolism in vivo. This kind of NMR spectroscopy with spatial
resolution related to the in vivo organism or related to live organs was called
"in vivo spectroscopy" or also "clinical nuclear magnetic resonance spectroscopy
(MRS)" in contrast to "high resolution NMR" in the test tube, which is usually carried
out in the laboratory, respectively in contrast to the mere magnetic resonance imaging
In the following, the physical basics of nuclear magnetic
resonance will be explained:
In MRS as well as in MRI the object to be examined (the
patient or the organ) is exposed to a strong, constant magnetic field. Thereby,
the nuclear spins of the atoms in the object, which were oriented randomly before,
are aligning themselves, building discrete energy levels. High radio frequency waves
can cause transitions between these energy levels. If a high frequency pulse e.g.
enables a steady state population of the levels, an induced signal can be obtained
after the switch off of the high frequency field. Because of application of inhomogeneous
magnetic fields initiated by so-called gradient coils, the object to be investigated
can be excited selectively and the signals can be spatially encoded.
In MRS the data sampling is usually realised in the so-called
time domain, the sampling of the MRI data in the so-called k-space (synonymous:
frequency space). The MR spectrum in the frequency domain, respectively the MRI
image in the so-called imaging space, is correlated with the sampled data by Fourier-transformation.
A volume excitation in the object is realised in the object by slice selective high
frequency pulses, namely by simultaneous application of gradient pulses. For the
excitation of a cuboid e.g. three slice selective high frequency pulses in three
orthogonal directions are applied in the MRS. Normally, these are three Sinc-shaped,
Gaussian-shaped or hyperbolic-shaped RF pulses, which are irradiated simultaneously
with rectangular or trapezoid gradient pulses in the object to be examined. The
irradiation of the RF pulses has to be effected by an RF antenna.
By the combination of said pulses a frequency spectrum
in the range of a nuclear specific resonance frequency is radiated in a well-defined
cuboid-shaped area of the object to be examined. The respective nuclei in this selected
range (volume of interest, VOI) react on their part with electromagnetic response
signals (electromotive force EMF), which are detected in the form of a sum signal
(free induction decay signal FID-signal), respectively in form of a (half) spin
echo signal by a special receiving condition of said RF antennas. This analogue
signal (FID or echo) is sampled by switching of an ADC (analogue-digital-converter),
digitalised and saved on a computational apparatus, respectively Fourier-transformed,
whereby a so-called "spectrum" can be displayed on a visualisation apparatus (monitor).
Both components of the measured signals (FID or echo signals)
characterise the projections of said oscillation behaviour of the nuclear magnetisation
in the x-y-plane of a stationary frame of reference (laboratory system of coordinates).
The temporary decay of the signal is determined by the
T2-weighted transversal relaxation. The transversal relaxation leads
to the disappearance of the time-dependent transversal magnetisation
whereas the T2-time - more particularly the T2*-time, which
considers local B0-field inhomogeneities &Dgr;B0 according
to the equation
- as a characteristic time constant is determining the decay of the FID or echo
signal. In the above equation, &ggr; represents the gyromagnetic ratio, which
describes the energetic coupling constant of the respective nuclei to the external
magnetic field and which is a firm constant of the respective nucleic species.
The complex and time-dependent (therefore three-dimensional)
FID or echo signal itself can be considered as the electromagnetic answer to one
or more circular high frequency exciting pulses, which have been irradiated into
the respective substance or the tissue to be examined before.
In the case of the substance or tissue consisting of only
one specific nucleic species (e.g. protons in pure water) and the RF excitation
pulse being irradiated with a frequency, which corresponds exactly to the Lamor
frequency of the protons (63,8 MHz at 1,5 Tesla), the measured FID respectively
echo signal of the water protons will not contain any har-monic/periodic parts (sinus-
or cosinus-shaped components), as in the (at 63,8 MHz) rotating referential system
a precession/rotation of the transversal magnetisation does not take place. (The
relative movement in the rotation direction equals zero). Measurable is only the
relaxation-dependent exponential reduction of the transversal magnetisation vector,
which constitutes a non-modulated exponential function (dashed line in Fig. 2A).
If the irradiated RF excitation pulse shows a frequency,
which does not exactly corresponds to the water protons (e.g. 63.8 MHZ + 400 Hz),
but provokes an excitation of the protons due to its pulse amplitude anyhow, the
measured FID respectively echo signal, at a referential frequency for the data acquisition
equalling the frequency of the RF pulse, will contain a harmonic part of 400 Hz,
which is - according to Fig. 2A - modulated to the exponential relaxation decay
In general, the substance respectively the object to be
examined (in the medical in vivo spectroscopy) will firstly not contain only one
nucleic species (1H, 31P, 13C), but a plurality of nucleic species to be analysed.
Secondly, the nuclei of the same species will show relatively to each other different
resonances (Lamor frequencies) due to their different integration into different
molecules (different chemical environment) and can be distinguished as so-called
In the (in vivo) proton spectroscopy the frequency range
of most metabolite signals is about 10ppm, the spectral width in the (in vivo) phosphor
spectroscopy is ca. 30 ppm and in (in vivo) 13C-spectroscopy the resonances in the
spectra are spread over an area of about 200 ppm. The indication of the changing
of the resonance frequency &dgr; relative to the system frequency (RF centre frequency
&ngr;0) in ppm (parts per million), i.e. in millionth of the resonance
frequency according to the equation
is advantageously independent of the strength of the magnetic field.
In general, the FID respectively echo signal thereby forms
a temporally dependent response signal - a so-called "signal imaging/representation
in the time domain" - in whose exponential process all resonances (&ohgr;x,
x∈N) of the excited nuclei in the respective metabolites are modulated superposedly
An FID, which according to Fig. 2A contains the frequency
response of only one metabolite, delivers according to Fig. 2B only one resonance
An FID, which contains e.g. the frequency responses of
three different metabolites, is shown in Fig. 3A. It can be seen, that the FID respectively
echo signal in Fig. 3A is encoded considerably more complex than the FID respectively
echo signal of Fig. 2A, which shows only one frequency. This encoding can by decrypted
by a Fourier-transformation and ordered by the respective resonance frequencies,
whereby according to Fig. 3B a three-component spectrum with so-called resonance
lines at &ohgr;0, &ohgr;1 and &ohgr;2 is obtained.
The Fourier transform of the FID respectively echo signals
(Fig. 2B, 3B) is generally referred to as spectrum. It is also referred to as "signal
imaging/representation in the frequency domain".
Although, as already mentioned, the gyromagnetic relation
&ggr; (equation (1)) is a firm constant of the respective nucleic species (e.g.
for the proton is &ggr;/2&pgr;=42,577 MHz/T), in the same (constant) outer magnetic
field slightly different resonance frequencies can be seen in NMR experiments, in
which the examined nuclei are integrated in different molecules. Responsible therefore
are the electrons in the molecule, which cause the chemical binding. They shield
the outer (external) magnetic field, so that the nuclei depending on the state of
binding "sees" different magnetic fields (BK), which causes the already
mentioned slight displacement of the respective resonance frequency and is referred
to as "chemical shift &dgr;K":
In a molecular complex there is often a plurality of resonance
lines, which can be assigned to single molecule groups. Quantitatively, according
to equation (4) the chemical shift is mostly given in ppm relative to a reference
Apart from the chemical shift, also a fine splitting of
the nuclei resonance lines in form of multiplet lines (doublets, triplets, quartets,
etc.) can be seen often. Responsible therefore is the magnetic interaction (spin-spin-coupling)
among the nuclei, which is not arranged over the space, but indirectly over the
electrons of the chemical binding. For the analysis of the spectra with a fine structure
usually the energy function (Hamilton operator Ĥ) with the interaction
(scalar energy coupling constant) between the different spin states
whose eigenvalues and eigenfunctions describe the measured spectrum corresponding
to the assumed molecular model. In this way, the structural clarification of (macro-)
molecules is advantageously realised in chemistry and biochemistry. In the medical
sector typical metabolites can be detected non-invasively on the basis of their
spectra in vivo.
In imaging the low sensitivity of magnetic resonance using
the proton signals of water is not a major issue as 1H nuclei have a
large magnetic moment and water is abundantly present in the body. In MR spectroscopy,
however, usually compounds at much lower tissue concentrations are observed and
often also many MR nuclei with interesting physiologic information (e.g.
31P, 13C, 15N) are less sensitive than the
1H nucleus. A known class of methods for detection improvement in NMR-spectroscopy
is known as polarisation transfer, in which the high population difference of two
or more energy levels of a particular nuclear spin system is transferred to the
energy levels of a less populated other nuclear spin system by spin-spin-coupling.
The principle of the polarisation transfer-based detection
improvement is explained in detail in the following:
Simplifyingly, the example contains a two-spin-system consisting
of each one sensitive and one insensitive (slightly sensitive) nuclei, e.g.
1H and 13C.
In a magnetic field B0 such nuclei (spin quantum
number S) are able to adopt each to two discrete energy states. The transition
between energy levels involves the absorption or emission of an electronic quantum
The allocation/population of the energy levels in the external
magnetic field B0 takes place according to the Boltzmann-statistic
Resulting therefrom is an excess of nuclei-magnetic moments
parallelly aligned to the magnetic field B0.
Decisive for the population difference between two states
Eq and Ep is the gyromagnetic relation &ggr; of the respective nuclei, which changes
its spin-adjustment/orientation during the transfer from Ep→Eq.
For states, which belong to the transfers of a sensitive nucleic species A (high
&ggr;), a greater population difference results than for states, which belong
to the transfers of an insensitive nucleic species X (low &ggr;).
The population in the term scheme of such an AX-system
consisting of a strongly sensitive nuclei (A) and a slightly sensitive nuclei (X)
is schematically shown in the figures 4A, 4B and 4C.
Figure 4A shows the state of equilibrium, in which the
two lowest energy levels (1) and (2) are populated the most (symbolised by bold
If an interchanging of the respective spin populations
is achieved by a (selective) population inversion for an A-line (A1 or A2) in the
NMR-spectrum, so the term scheme of Fig. 4B which now shows fortified absorption
(X1) and fortified emission (X2) for the X-transfers, respectively the term scheme
of Fig. 4C whereby X1 shows fortified emission and X2 fortified absorption, becomes
valid. In both cases (figures 4B, 4C) the population balance is perturbed by selective
population inversion between the states (1) and (3) respectively between the states
(2) and (4).
The population difference corresponding to the signal intensity,
which was beforehand decisive for the sensitive nuclei, is now valid for the insensitive
nuclei. This phenomenon is referred to as polarisation transfer, which is used for
enforcing the signal of NMR-insensitive nucleic species (X).
Of general interest is thereby the sensitivity improvement
of 1H-coupled spectra of insensitive nuclei, as e.g. 13C (but
also 15N or 31P), i.e. the intensity increasement of XAn-spin
systems with A=1H und X=13C.
The diagram of an energy level of a CH-spin system (n=1)
with different coupling is shown in figures 5A, 5B and 5C.
Figure 5A shows the four energy levels 1, 2, 3 and 4 without
coupling onto the external magnetic field B0, which are possible due
to different C-H-spin modulations, i.e. for the scalar energy-coupling-constant
J=O. As in this case the 1H-transfers 3→1 and 4→2, respectively
the 13C-transfers 2→1 and 4→3 are energetically equal,
only one 1H-line and one 13C-line are resulting in the spectrum
(no splitting, respectively no hyperfine structure).
In figures 5B and 5C a different example is shown, in which
an energetic coupling of the C-H-spin states takes place, whereby in case of figure
5B the energy levels of the parallel spin states (↑↑,↓↓)
are increased by J/4 and the energy levels of the antiparallel spin states (↑↓,
↓↑) are decreased by J/4. In figure 5C an exactly inverse example
is shown. The coupling &ggr;1H
leads in every case to each two energetically different transfers of the
respective atomic nucleic species, which leads to a double fine structure splitting
in the spectrum, i.e. to two directly neighbouring spectral lines in form of a doublet.
Each nucleic species alone thereby experiences an overall energy changing of J.
To calculate the population relations (relative population-respectively
transfer probability) for the polarisation transfer and which is thereby relevant
for the signal enhancement to be effected, it is advantageous, to regard the term
scheme of figures 4A and 4C more closely, i.e. quantitatively (see figures 6A, 6B,
In figure 6A the lowest energy level features an energy
(which is proportional to the population probability), while the other energy levels
feature energies respectively population probabilities of
in ascending order, corresponding to the respective coupled spin states (&agr;&agr;
= ↑↑= parallel to B0), (&agr;&bgr; = ↑↓),(&bgr;&agr;
=↓↑), (&bgr;&bgr; = ↓↓ = antiparallel to B0).
After a suitable (spin) preparation of the system by irradiation
of suitable electromagnetic high frequency pulses in the context of a defined pulse
sequence, energy can be added selectively to the system, in a way that the &agr;&bgr;-coupling
changes into the energetically higher &bgr;&bgr;-coupling. The system advantageously
comprises therefore after the preparation spin-spin-pairs, which are parallel (&agr;&agr;
= ↑↑) and antiparallel (&bgr;&bgr; = ↓↓) to the
magnetic field B0.
If, for the sake of clarity, one add to the energy levels
the constant energy amount of
the energy states &ggr;H
, &ggr;H, &ggr;
and 0 are obtained. If further the relative relation of the nucleic sensitivities
of 1H and 13C (&ggr;H
=4 and &ggr;C
=1) is taken into account, so the relative values of 5, 4, 1 and 0 are obtained
for the energy levels according to figure 6B. These values correspond as well, as
already mentioned, to the relative population probabilities respectively the relative
populations, as the magnetic moment µ characterising the sensitivity
defines the differences of the energy levels as well as the population probabilities
(according to Boltzmann).
As can be seen clearly in figure 6B, the population difference
of the 13C-transfers is relatively low (&Dgr;=1-0=+1; &Dgr;=5-4=+1)
in the unexcited system. According to that the 13C-doublet features a
low NMR-signal intensity compared to the 1H-doublet. If the system, however,
is forced into a higher-energetic state by energy transfer (alignment of the spin-pairs
antiparallel to B0), population differences of 13C-transfers
are resulting, which lead to an emission enhancement of &Dgr;=1-4=-3 as well as
an absorption enhancement of &Dgr;=5-0=+5 in the spectrum (figure 6C).
This signal enhancement of an X-doublet in the NMR-spectrum
(e.g. X=13C) is shown in figure 7A. The unit of the ordinates was chosen
randomly. Important is the significant enhancement of the two X-doublet lines.
The enhancement to a 3-atomic AX-spin system (e.g. to a
CH2-group) leads to a significantly more complex term scheme of the energy
levels and - as can be shown - to an X-triplet with the relevant intensities (1)-(2)-(1)
in the spectrum (figure 7B). A signal enhancement leads to values of (-7)-(2)-(9)
in this system.
The intensity enhancement, which is obtained in the general
enhancement to AnX-spin systems (A=1H, X=13C),
can be calculated by comparison with Pascal's Triangle according to Figs. 8A and
Line numbers and relative intensities for an X-multiplet
of an AnX-group (A=1H) at Boltzmann-distribution (figure 8A)
and after population inversion (figure 8B) are shown. The respective triangle is
obtained by combining the (integral) energy level transfers of the underlying term
The preparation of the spin system and thereby the realisation
of the polarisation transfer can be achieved by using different RF pulse sequences.
Most common is the INEPT-method (
Insensitive Nuclei Enhanced by Polarization Transfer, Morris, Freeman, J.
Am. Chem. Soc. 101, 760-762 (1979)
Further methods are e.g. Refocused-INEPT, DEPT (Distortionless
Enhancement by Polarization Transfer), SINEPT, etc.
Generally, all these methods are based - as will be explained
later in more detail - on the concurrent appliance (irradiation) of RF pulses on
the different frequencies of the participating nucleic species (i.e. for example
1H, 13C). This results in the disadvantage, that NMR apparatuses,
which are not able to concurrently send in the different frequencies of the participating
nuclei, are also not able to execute NMR experiments with polarisation transfer.
It is therefore an object of the present invention to provide
a method and an apparatus which is able to execute said method, which enables NMR
experiments with polarisation transfer without the concurrent appliance of RF pulses
of different frequencies.
This object is solved by the present invention as claimed
in the independent claim. Further advantageous features are claimed in the dependent
According to the present invention, a method is claimed
for improvement of the detection in NMR spectroscopy or spectral editing of molecular
fragments by polarization transfer in which the high population difference of two
or more energy levels of a particular nuclear spin system (A) is transferred to
the energy levels of an other nuclear spin system with lower spin population difference
all HF pulses to be irradiated are irradiated sequentially, i.e. with defined time
interval to each other, so that at no time of the sequence said (frequency -) different
phase coherent HF pulses are irradiated concurrently respectively in an overlapping
manner, whereby the sequential succession of said HF pulses realizes a polarization
transfer between said two spin systems of atomic nuclei involved (A), (X), wherein
the sequence of said HF pulses in each domain of the respective nuclei is completely
The method modifies the HF-pulse ordering of a DEPT sequence.
In particular, the HF pulse sequence comprises the steps
- irradiating a first A-selective 90x
o(A)-HF-pulse for excitation of the nuclei (A) with high spin population
- irradiating a second A-selective 180y
o(A)-HF-pulse after a time &tgr;1+&tgr;2 starting
from center of the first HF pulse,
- irradiating a third X-selective 90x
o(X)-HF-pulse after the time &tgr;1+2&tgr;2
starting from center of the first HF pulse,
- irradiating a fourth A-selective &agr;y(A)-HF- pulse after the
time &tgr;1 starting from center of the third HF pulse,
- irradiating a fifth X-selective 180x
o(X)-HF- pulse after the time &tgr;3 starting from center
of the fourth HF pulse,
- acquirering of the X-nuclear resonance signal by detection of the FID signal
after a time &tgr;3+&tgr;1 starting from center of the
fifth HF pulse.
For the time interval &tgr;1 applies &tgr;1=1/2J,
whereby J represents the XA coupling constant, whereby, according to a special embodiment
of the invention, long range coupling is used for polarization transfer.
Advantageously for sequential succession of RF pulses,
the time interval &tgr;2 comprises at least the sum of the half second
o(A)-HF-pulse and the half third X-selective 90x
Further advantageously the time interval &tgr;3
comprises at least the sum of the half fourth A-selective &thgr;y(A)-HF-
pulse and the half fifth X-selective 180x
Further advantageously &tgr;2 and &tgr;3
are chosen as independent variables in order to influence the spectral shape of
spin systems, which have strong homonuclear couplings (i.e. like ABX systems).
Further advantageously the coupling for the X-multiplet
of an AnX group is regarded, whereby n=1,2,3.
Further advantageously the species of atomic nuclei (A)
with high spin population difference represents 1H, 13C,
15N or 19F -nuclei and/or the species of atomic nuclei (X)
with low spin population difference represents 13C, 31P,
15N, 19F or 1H-nuclei.
Further claimed is an apparatus which is suitable for the
execution of a method according to the previous claims 1 to 11.
Additionally an apparatus is claimed according to claim
12, having only a single broadband transmit channel which is phase coherent in order
to enable polarisation transfer and/or an apparatus according to claim 12, having
only a single broadband transmit channel which is phase-continuous where &tgr;2
and &tgr;3 can be chosen such to obtain the correct phases for all
rf pulses in order to enable polarisation transfer.
Finally an apparatus is claimed according to claim 12 to
14 which is suitable for the execution of a method according to the claims 1 to
11 that can be combined with spatial localisation methods with magnetic field gradients
and/or radiofrequency coils.
For sequential succession of RF pulses, the time interval
&tgr;2 comprises the sum of the half second A-selective 180y
o(A)-HF-pulse and the half third X-selective 90x
o(X)-HF-pulse and the time interval &tgr;3 comprises the
sum of the half fourth A-selective &agr;y(A)-HF- pulse and the half
fifth X-selective 180x
In special cases the coupling for the X-multiplet of an
AnX group is regarded, whereby n=1,2,3.
More particular the invention is advantageously directed
to a method where
the high sensitive species of atomic nuclei (A) represents 1H-nuclei
the low sensitive species of atomic nuclei (X) represents 13C-nuclei.
A magnetic resonance imaging apparatus which is suitable
for the execution of a method according to the claims 1 to 22 is also claimed and
Further advantageous features of the present invention
are now explained by the embodiments with respect to the enclosed drawings.
- Fig. 1 shows a schematic view of an apparatus for magnetic resonance imaging,
- Fig. 2A shows the temporal course of the cross-/transverse-magnetisation, which
is characterised by a single resonance, in form of an FID-signal,
- Fig. 2B shows the frequency spectrum according to Fig. 2A generated by Fourier
- Figure 3A shows an FID-signal, which comprises three resonances,
- Fig. 3B shows the frequency spectrum according to Fig. 3A with its three resonance
- Fig. 4A shows a simplified term scheme of an AX-system consisting of a sensitive
nucleus (A) and an insensitive nucleus (X) in the state of balance,
- Fig. 4B shows the AX-term scheme in a disturbed balance after selective population
inversion between the states (1) and (3),
- Fig. 4C shows the AX-term scheme in the disturbed equilibrium after selective
population inversion between the levels (2) and (4),
- Fig. 5A shows the energy level diagram of an CH-spin system without coupling,
- Fig. 5B shows the energy level diagram of an CH-spin system with positive coupling
- Fig. 5C shows the energy level diagram of an CH-spin system with negative coupling
- Fig. 6A shows a quantitative view of the term scheme according to Fig. 4A,
- Fig. 6B shows the term scheme according to Fig. 4A respectively 6A in a concise
view of the relative population probability,
- Fig. 6C quantitatively shows the effect of the polarisation transfer on the
signal enhancement in the term scheme of Fig. 4C,
- Fig. 7A shows the signal enhancement of an X-doublet in the NMR-spectrum,
- Fig. 7B shows the signal enhancement of an X-triplet in the NMR-spectrum,
- Fig. 8A shows the Pascal triangle of the relative intensities of a multiplet
according to the Boltzmann-distribution,
- Fig. 8B shows the Pascal triangle of the relative intensities of a multiplet
after population inversion,
- Fig. 9A shows the RF-pulse sequence of the DEPT-method for an AX-system (1H,
13C) according to the state of the art,
- Fig. 9B shows the effect of the RF-pulse sequence according to Fig. 9A on the
A- and X-magnetisation in a vector diagram (vector diagram of protons and carbons),
- Fig. 10A shows the RF-pulse sequence of the DEPT-method for an AX-system according
to the state of the art,
- Fig. 10B shows a modification of the RF-pulse sequence in the DEPT-method for
an AX-system according to the present invention,
- Fig. 11 shows the signal enhancements for 13C doublets, triplets and quartets
as a function of the DEPT-pulse-flip-angle &thgr;,
- Fig. 12 shows the signal enhancements of localized DEPTUPS (Distorsionless Enhacenment
by Polarization Transfer Using Pulses Sequentially) for 13C resonances in the spectra,
- Fig. 13 shows a localized DEPTUPS spectrum with 13C signals of different metabolites
in human brain at 3T appearing upon 13C-1 glucose infusion. Frequency selective
1H rf pulses were used combined with B0 gradients for localization.
The methods of the clinical MR-spectroscopy primarily differ
from those of the conventional MR-imaging only in that in addition to the spatial
resolution, the chemical shift, respectively the hyperfine structure, is to be resolved
as well. This can be realised by conventional magnetic resonance imaging apparatuses,
which is why these are preferably used in the clinical MR-spectroscopy and the method
according to the present invention - modification of NMR-experiments, which use
polarisation transfer for detection enhancement of insensitive nuclei - is to be
primarily implemented on such apparatuses.
It is to be noted, however, that the method according to
the present invention can also be applied to high-field-in-vivo-MR-systems (momentarily
up to 7 Tesla for human applications and 17 Tesla for other applications), which
are isolatedly developed and used, as well as to high resolution NMR-spectrometers.
Fig. 1 shows a schematic illustration of a magnetic resonance
imaging (magnetic resonance tomography) apparatus for generating a magnetic resonance
spectrum of a subject according to the present invention. The basic structure of
the nuclear magnetic resonance imaging apparatus corresponds to that of a conventional
imaging apparatus (with the difference described below). A basic field magnet 1
generates a temporally constant, strong magnetic field for the polarisation or alignment
of the nuclear spins in the examination region of a subject such as, for example,
part of a human body to be examined. The high homogeneity of the basic magnetic
field required for the magnetic resonance measurement is defined in a spherical
measurement volume M into which the parts of the human body to be examined are introduced.
For supporting the homogeneity demands and, in particular, of eliminating time-invariable
influences, shim plates of ferromagnetic material are attached at suitable locations.
Time-variable influences are eliminated by shim coils 2 that are driven by a shim
power supply 15.
A cylindrical gradient coil system 3 that is composed of
three sub-windings is introduced into the basic field magnet 1. Each sub-winding
is supplied with power by an amplifier 14 for generating a linear gradient field
in the respective direction of the Cartesian coordinate system. The first sub-winding
of the gradient field system 3 generates a gradient Gx in the x-direction, the second
sub-winding generates a gradient Gy in the y-direction and the third sub-winding
generates a gradient Gz in the z-direction. Each amplifier 14 has a digital-to-analogue
converter that is driven by a sequence controller 18 for generating gradient pulses
at the correct time.
Located within the gradient field system 3 is a radio frequency
antenna 4 that converts the radiofrequency pulses output by a radiofrequency power
amplifier 10 into a magnetic alternating field for exciting the nuclei of the examination
subject or of the region under examination in the subject. The radiofrequency antenna
4 is composed of one or more RF transmission coils and one or more RF reception
coils in the form of a preferably linear arrangement of component coils. The RF
reception coils of the radiofrequency antenna 4 also convert the alternating field
emanating from the precessing nuclear spins, i.e. the nuclear magnetic resonance
echo signals (usually produced by a pulse sequence composed of one or more radiofrequency
pulses and one or more gradient pulses), into a voltage that is supplied via an
amplifier 7 to a radiofrequency reception channel 8 of a radiofrequency system 22.
The radiofrequency system 22 further has a transmission channel 9 in which the radiofrequency
pulses for the excitation of the nuclear magnetic resonance are generated. The respective
radiofrequency pulses are defined digitally as a sequence of complex numbers on
the basis of a pulse sequence in the sequence controller 18 prescribed by the system
computer 20. The real part and the imaginary part of this number sequence are supplied
via respective inputs 12 to a digital-to-analogue converter in the radiofrequency
system 22 and are supplied therefrom to a transmission channel 9. In the transmission
channel 9, the pulse sequences are modulated on a phase coherent radiofrequency
carrier signal having a base frequency corresponding to the resonant frequency of
the nuclear spins in the measurement volume.
The switching from transmission to reception mode ensues
via a transmission-reception duplexer 6. The RF transmission coil of the radiofrequency
antenna 4 emits the radiofrequency pulses for the excitation of the nuclear spins
into the measurement volume M and samples resultant echo signals via the RF reception
coils. The correspondingly acquired magnetic resonance signals are phase-sensitively
demodulated in the reception channel 8 of the radiofrequency system 22 and are converted
via respective analogue-to-digital converters into real part and imaginary part
of the measured signal, which are respectively supplied via outputs 11 to an image
computer 17. The image computer 17 reconstructs an image from the measured data
acquired in this way. The administration of the measured data, the image data and
the control programs ensues via the system computer 20. On the basis of a prescription
with control programs, the sequence controller 18 controls the generation of the
respectively desired pulse sequences and the corresponding sampling of k-space.
In particular, the sequence controller 18 controls the temporally correct switching
of the gradients, the emission of the radiofrequency pulses with defined phase and
amplitude as well as the reception of the nuclear magnetic resonance signals. The
time basis for the radiofrequency stem 22 and the sequence controller 18 is made
available by a synthesiser 19. The selection of corresponding control programs for
generating a magnetic resonance image ensues via a terminal (console) 21 which comprises
a keyboard as well as one or more picture screens.
With the described MRI-apparatus the most different MR-spectroscopy
sequences can be generated and MR-spectroscopic localisation methods can be realised
for clinical applications. The described MRI-apparatus according to the present
invention shall be able to generate pulse sequences, in which the RF pulses of different
frequencies do not overlap each other temporally.
This particularly concerns NMR-experiments, which use a
polarisation transfer for signal enhancement.
Such methods tend to energetically prepare coupled spin
systems of differently sensitive nuclear species (such as in CH, CH2,
NH, NH2, ...) such, that the energy level population difference of nuclear
spin species is increased and thereby increases emission and/or absorption, which
leads to a significant signal enhancement of the nuclear species in the NMR-spectrum.
An important pulse sequence in NMR-spectroscopy which relies
on the cross-polarization phenomenon respectively polarization-transfer for achieving
sensitivity enhancement is known as "Distortionless Enhancement by Polarization
Transfer" (DEPT). In the following the effect of the DEPT pulse sequence on a AX-system
respectively on a CH-system is considered. The pulse sequence employed on the
1H and 13C nuclei and the effects on the corresponding magnetization
vectors according to the state of the art are shown in figures 9A, 9B and 10A. The
modified pulse sequence according to the present invention as employed on the A
(1H) and X (13C) nuclei and the effects on the corresponding
magnetization vectors will be explained later by means of figure 10B.
It is noted that in the vector diagram the respective magnetization
is illustrated in rotating frames. After an equilibrium delay T1 (not illustrated),
which allows a Boltzmann equilibrium of the protons to be reached, a 90x
o pulse is applied to the A (e.g. 1H) nuclei (note that a)
to h) in the pulse sequence of figure 9A correlate with a) to h), in the vector
diagrams of figure 9B giving the corresponding effects on the magnetization vectors
of the 1H and 13C nuclei) which causes the magnetization of
the protons to be oriented along the y-axis (a) in figure 9B). In contrast to other
sequences (e.g. INEPT, SINEPT), a time delay of &tgr;=1/2J is now inserted during
which the transverse magnetization of the 1H nucleus is modulated through
coupling with the 13C nucleus. At the end of the &tgr;=1/2J time period,
the two doublet vectors of the 1H nuclei are found to have a phase difference
of 180°, and they lie along the x'-axis (b) in figure 9A). A 180 yo
pulse is now applied to the protons in order to refocus any inhomogeneities. Simultaneously
a 90 x
o pulse is applied to the 13C nuclei which creates transverse
magnetization of these nuclei along the y-axis (c) in figure 9B).
Since there is no magnetization of the 1H or
13C nuclei along the z-axis, the two are now decoupled, and during the
following &tgr;=1/2J delay period, the vectors of both nuclei remain static in
the rotating frames (see d) and e) in figure 9B). A proton pulse &thgr; (the length
of which is adjusted depending on the number of attached protons and the spectrum
desired to be recorded) is then applied which serves to polarize the 1H
magnetization. The population transfer occurs at this stage, since the polarization
of protons caused by the proton pulse &thgr; also effects the 13C nuclei
due to 13C -1H coupling. An intensification of the
13C magnetization vectors therefore takes place. In figures 9A, 9B the
length of this pulse has been kept at 90° which results in the 1H
magnetization coming to lie along the z-axis (f) in figure 9B). At the same time
this proton pulse also causes a polarization of the 13C nuclei (g) in
figure 9B). Since z-magnetization now exists in the 1H nucleus, spin-spin-coupling
can take place with the 13C nucleus, resulting in a refocusing of the
13C magnetization vectors during the last 1/(2J) period (h) in figure
9B). The 13C magnetization can now be detected at t=3T either as doublet
or, if 1H decoupling is simultaneously applied, as a singlet.
The signal enhancements as a function of the variable &thgr;
pulse for CH3, CH2 and CH carbons are shown in figure 11.
An experiment with &thgr;=90° results in a spectrum containing peaks for CH
carbon atoms only. A 135° &thgr; pulse, on the other hand, affords a spectrum
with CH3 and CH carbon atoms bearing positive amplitudes and CH2
carbon atoms with negative amplitudes. If the value of the &thgr; pulse is kept
at 45°, then CH3, CH2 and CH carbons all appear with
positive amplitudes. In this way variations in the value of &thgr; can be used
for spectral editing.
In contrast to other methods (INEPT, SINEPT) DEPT spectra
afford multiplets, which have the same appearance as in the normal spectrum. Moreover,
the acquisition of spectra with other methods (INEPT, SINEPT) requires knowledge
of J values for setting delays between pulses and variations in the settings would
result in different enhancements in the for example decoupled INEPT spectra. DEPT
spectra, on the other hand, depend on variation in the length of the &thgr; pulse
and are independent of the exact delay times 1/(2J) between the pulses so that an
error of ±20% in J values would still afford good DEPT spectra.
Clinical MR scanners are in general not equipped with a
second transmit RF channel making conventional polarization transfer techniques
like Distortionless Enhanced Polarization Transfer (DEPT) impossible. According
to the state of the art this problem is solved by adding a separate RF channel to
the MR system that enables simultaneous transmission on the spins of two different
nuclei (like 13C and 1H). As such an additional RF channel is expensive and requires
extensive effort to integrate into a clinical MR system, alternatives are required.
According to the present invention it is suggested to modify
the conventional DEPT sequence in such way that the irradiated HF-pulses do not
overlap in time, while maintaining a best possible symmetry in the A-domain as well
as in the X-domain. This means that, in contrast to the conventionally DEPT sequence
which is characterized by only one time delay &tgr;1 with &tgr;1=1/2J,
new time delays must be introduced taking into consideration firstly the behavior
of precession of the specific magnetization of the respective species of nuclei
and secondly the maintenance of total symmetry in the domain of both species of
nuclei. This new modified DEPT-sequence, characterized by using RF pulses on a single
transmit channel, therefore called DEPTUPS (DEPT-Using-Pulses-Sequentially) enables
the use of polarization transfer (PT) without the need of an expensive additional
RF transmit channel. A comparison between direct-13C-NMR-spectroscopy and DEPTUPS
is illustrated in figure 12.
The great advantage of DEPT over other PT-based techniques
(INEPT, SINEPT, etc.) is thereby that different species with different chemical
shifts and J-couplings, which is the case for clinically interesting metabolites,
can be detected simultaneously.
Figure 10B shows such a modified DEPT sequence according
to the present invention for a 1H and 13C nuclei system:
whereas the first and most important time interval is determined by the AX- respectively
acquiring of NMR signal ,
o-inversion-pulse for the A-spin-system, however, does not begin before
the time delay &tgr;2 which is determined by the sum of the half second
o(A)-HF-pulse and the half third X-selective 90x
o(X)-HF-pulse and which also (together with &tgr;1) determines
the time distance between the very first two pulses 90x
o(A) and 180y
o(A). In order to achieve total symmetry in the A-domain without overlapping,
the &thgr;y(A)-pulse has to be irradiated &tgr;1 after
the first pulse in the X-domain 90x
o(X). The fifth and also the last pulse in this sequence scheme is a
o(X)-HF- pulse irradiated after the time &tgr;3 starting
from the center of the fourth HF pulse &thgr;y(A). Since the fourth
pulse &thgr;y(A) normally has not the same pulse width than the third
o(X), and also the fifth pulse 180x
o(X) has not the same pulse width than the second pulse 180y
o(A), the time delay &tgr;3 is generally different from
the time delay &tgr;2. In order to achieve total symmetry in the X-domain
without overlapping with the 180x
o (X)-pulse to be irradiated &tgr;1+&tgr;3
after the third pulse 90x
o (X) in the X-domain, the acquisition of the X-nuclear resonance signal
(in form of a FID or an echo) has to be performed after a time &tgr;3+&tgr;1
starting from center of the fifth HF pulse 180x
Owing to this high symmetry of the sequence according to
the present invention, a polarization transfer effect is realized not only to one
nucleus in one type of molecule but to many nuclei integrated in different kinds
of molecules and are therefore exhibiting resonances over a wide spectral range,
because of the wide range of chemical shift, as can be seen in figure 13 by means
of a 13C-MR-spectrum of the human brain at 3T obtained during 50% 13C-1
labelled glucose infusion.
The reason for the occurrence of resonances over a wide
range of the DEPT/DEPTUPS spectrum is: the first 90°-pulse excites all nuclei
of the corresponding nuclear species. Depending on the chemical shift the spins
of nuclei in different kinds of molecules dephase with a different speed. When giving
a 180°-pulse, a overall rephasing takes place, so that after the time of dephasing
and rephasing all spins with different chemical shift are exactly in phase at the
same duration of time starting at dephasing. If then an other RF-pulse is exciting
the nuclei, it is certain that the spins of nuclei of all molecules have the same
phase and experience the full polarization transfer effect.
Taken together the new DEPTUPS-sequence shows multiple
advantages. The different potential applications in (N)MR-Spectroscopy are:
- Monitoring 13C signals of compounds, which are otherwise difficult
to resolve by conventional 1H-NMR-spectrocopy, due to the strong signal
- Monitoring signals of carbons labelled with 13C to uncover (abnormal)
metabolic conversions. This is for instance of interest in brain diseases. New strategies
are now being explored in order to make this clinically feasible. There have recently
also been proposals for a new head coil for improved 13C MRS of the human
brain. With the proposed innovation of a single RF channel, a DEPT sequence becomes
more realistic and cost-effective in the clinical application;
- An emerging new field is MRI with hyperpolarisation of 13C (or other
(N)MR sensitive nuclei) in compounds to boost sensitivity. Currently this is mostly
performed with carbons, which are not attached to protons in order to take advantage
of the long T1 values of these spins. However, molecular conversions may cause these
carbons to become attached to protons and then polarization transfer may further
enhance their signal. Moreover, due to the presence of long-range couplings from
protons to (carbonyl) carbons (J-coupling arise from 2-15Hz), polarisation transfer
may also be effectuated for these carbons;
- The present invention is generally applicable to polarization transfer of any
nucleus to another nucleus. In this way high population spin differences of any
nuclei created by any method can be advantageously used to enhance the sensitivity
of any other nuclei. The only restriction is that the increase in sensitivity is
not counterbalanced by T2 loss, e.g. l/J<(5xT2). For instance, polarisation transfer
of 1H to 31P nuclei was recently demonstrated in vivo by a
so called INEPT approach [
Mancini et al. MRM 54:1065-1071; 2005
]. Several of the disadvantages mentioned in this paper for the INEPT approach
(SAR, bandwidth) can be circumvented by the proposed innovation using the DEPT sequence.
This is of interest, as the polarization transfer enables an improved visualisation
of phosphorylated membrane compounds (e.g. phosphocholine) which are central in
tumor and cell growth (in contrast to 1H-NMR-Spectroscopy which only
visualises bulk choline compounds).
- Hochfrequenz-Empfangskanal (erster Demodulator)
- zweiter Demodulator