NMR imaging method and apparatus

A method and apparatus for imaging the concentration of paramagnetic species inside a sample is disclosed wherein a sample is placed inside an NMR imager and an additional microwave field is introduced. A microwave field is chosen in such a way that there is a simultaneous resonance of nuclear spins (protons) and electrons in the same main magnetic field. The microwave signal is modulated which provides a modulation transfer to the intensity of the NMR signal. The modulation is extracted from the NMR signal to produce an image representative of the local electron spin resonance (ESR) and thereby the concentration of paramagnetic species in the sample. In addition, electrical activity of the brain can be detected and measured by measuring the broadening of the width of NMR spectral lines. A discharging neuron in the brain introduces an inhomogeneity in the magnetic field which reveals itself as a broadening of resonance lines which can be measured to determine the neuron discharge current flux.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention is directed to NMR imaging techniques for imaging 
paramagnetic species inside a sample and for determining information on 
the electrical activity of the brain of a subject. 
2. Description of the Prior Art 
Electron spin resonance (ESR) has been used to measure the concentration of 
paramagnetic species in samples for many years. As disclosed in U.S. Pat. 
No. 3,090,003, the ESR technique uses microwave frequency signals 
transmitted to a resonator cavity within which is placed the sample. The 
cavity is within a homogeneous magnetic field. The measurement of the 
concentration of paramagnetic species, such as radicals, transition metal 
atoms, excited molecules, etc., inside a man or a large animal has long 
been regarded as impossible because of the difficulty in constructing a 
cavity that would encompass the large volume of tissue, particularly when 
dealing with a living person. 
In addition, imaging of paramagnetic species using the ESR technique is in 
a much earlier stage of development than NMR. For example, spatial 
distributions of paramagnetic species have been measured by a spectrometer 
using ESR techniques in U.S. Pat. No. 4,280,096. Gradient coils similar to 
those used in NMR are used to produce one-dimensional images. NMR and ESR 
techniques have been combined to record and observe spectra in electron 
nuclear double resonance (ENDOR). An ESR spectrometer is adapted to 
resonate nuclear spins by adding a radio frequency oscillator to the 
system. Examples of the ENDOR technique can be seen in U.S. Pat. Nos. 
3,532,965 and 3,250,985. 
In the prior art gyromagnetic systems, paramagnetic species are not 
detected directly by means of their electron resonance but by their effect 
on the relaxation times of nuclei undergoing nuclear spin resonance. The 
direct observation of ESR in large objects has been frustrated because of 
difficulties in designing a resonator with sufficiently high quality 
factor (Q) of dimensions many times larger than the operating wavelength. 
Recently, Holder proposed to use ESR at about 1 GHZ to obtain images of the 
human head, using a technique derived from NMR imaging; referring to 
Holder, The Potential Use of ESR or Impedance Measurement to Image 
Neuronal Activity in the Human Brain, Electric and Magnetic Fields in 
Medicine and Biology, Conference Proceedings, London, 1985, IEEE 
Conference Publication 257. Localization of the neural activity of the 
brain is at present possible only by means of electroencephalography, but 
the precision of localization is rather low, at most of an order of 1-2 
cm. The deeper structures in the brain are even less accessible and the 
localization rapidly deteriorates. Furthermore, localization by means of 
EEG lacks a reference grid or an anatomical reference to known parts of 
the brain. At this time, most accurate in localization of averaged 
metabolic activity is Positron Emitter Imaging, but it is by no means 
certain that the metabolic map will correspond to the electric activity 
map. 
However, from the viewpoint of neurology, even more useful information can 
be obtained from the reconstructed images of the electrical firing of 
nerve cells in the human brain, since this would allow analysis of 
functional activity of neuroatomical pathways which cannot be achieved 
with the current techniques. Holder investigated the possibility that 
neuronal firing can be detected by a form of electromagnetic radiation 
which can then be reconstructed to form three-dimensional images of this 
functional activity. Holder teaches the use of ESR and impedance imaging 
as giving the best results. Holder states that NMR, being well established 
for spectroscopy and imaging, could be employed to detect neuronal firing, 
but that current flux from ions moving across the neuronal membrane would 
be too small to be detectable by NMR. 
SUMMARY OF THE INVENTION 
The present invention is directed to magnetic resonance imaging (MRI) 
methods and apparatus for measuring and imaging the concentration of 
paramagnetic species from a sample. In addition, an MRI method is 
disclosed for detecting and measuring electrical activity of the brain. In 
one embodiment of the present invention, an imaging technique termed 
Nuclear Electron Double Resonance (NEDOR) starts with a conventional NMR 
imaging apparatus and includes a high frequency resonator or radiator such 
as is used in ESR techniques. A sample, such as a human body, is placed 
inside the main magnetic field coils of the NMR imager. A radio frequency 
(RF) pulse is applied via RF coils to excite to resonance a plurality of 
nuclear spins producing an NMR signal. A microwave (MW) pulse is applied 
via a high frequency resonator or radiator to excite to resonance a 
plurality of electron spins within the sample. The RF and MW pulses 
simultaneously resonate the nuclear and electron spins within the sample. 
The intensity of the MW signal is modulated, which translates into a 
modulation of the intensity of the NMR signal. The modulation is extracted 
from the NMR signal to produce an image representative of the local ESR 
and thereby the concentration of paramagnetic species in the sample. In a 
preferred embodiment, the RF coil is also used as the MW resonator. 
Electron spin resonance is the study of properties and molecules containing 
unpaired electrons by observing the magnetic fields at which the electrons 
come into resonance within an applied radiation field of definite 
frequency. Nuclear magnetic resonance monitors the reversal of nuclear 
magnetic moments wherein the nucleus with a net spin has been excited to 
resonance. For biological and other purposes, it is sometimes necessary to 
artificially introduce the unpaired electrons, into the sample in the form 
of paramagnetic tracers. In one embodiment, paramagnetic tracers are 
introduced into the sample to improve the differentiation between 
different tissues and improves detection of pathological changes. 
In a further embodiment, a plurality of NMR spectral lines having a defined 
width are derived from the modulated NMR signal. It has been determined by 
the applicant, that the width of the spectral lines is broadened due to 
the electric activity in the brain. The discharge of a neuron in the brain 
introduces an inhomogeneity into the main magnetic field. The contribution 
of the spectral line width due to the electric activity is measured, which 
can provide a measurement of the intensity of neuron discharges in the 
brain.

DETAILED DESCRIPTION OF THE INVENTION 
Referring now to the drawings, FIG. 1 shows an MRI apparatus having main 
field coils 10 for generating a homogeneous magnetic field. An RF coil 12 
is arranged within the main fields coils 10 with its axis parallel to the 
axis of the main field coils. The coil 12 may act as both the radio 
frequency coil and the ERS microwave radiator. Alternatively, a separate 
high frequency radiator may be provided at 14 such as a horn, slotted 
transmission line or other equivalent structure. 
In the former embodiment, the radio frequency coils of the NMR imager would 
be designed such that they can also perform the function of the high 
frequency resonator. The saddle-shaped coil structures utilized for the RF 
field can be utilized as both a distributed transmission line and 
resonator. The helicoidal coils can incorporate a slot system which can be 
used to radiate very high frequencies into the object placed inside the 
turns of the main field. 
The NMR imager includes a pulsed RF source 16 and an NMR receiver 18. A 
switch 20 operates to permit selective transmission of the RF pulse and 
reception of the NMR signal from the sample. A synthesized super high 
frequency power generator 22 generates the microwave frequency pulse 
signal to the resonator. The microwave pulse in this application refers to 
a burst of electromagnetic energy of a frequency suitable to cause ESR 
transitions. A wave filter 24 is provided to permit only the desired 
frequency signal to be applied to the sample. A modulator 26 is coupled to 
the generator 22 to modulate the MW output signal. 
The operation of the invention will first be described through the laws of 
electromagnetics.Nuclei with a total magnetic moment .mu. placed in a 
magnetic field H has an interaction energy described by the Hamiltonian: 
EQU =.mu.H (1) 
Assuming the field to be in the z-direction, the eigenvalues of energy are 
EQU E=.gamma..sub.p hH.sub.z m m=I, I-1, . . . ,-I (2) 
where h=Planck's constant and m=angular momentum 
For hydrogen I=1/2 and m=1/2, -1/2 transition between these two states has 
an energy of 
EQU .DELTA.E=.gamma..sub.p hH.sub.z (3) 
or frequency associated with transition 
EQU .omega.=2.pi.f=.gamma..sub.p H.sub.z (4) 
The factor .gamma..sub.p for hydrogen nucleus (proton) is equal to 
2.6753.times.10.sup.8 radian.sec.sup.-1.Tesla.sup.-1. For a single 
electron in external magnetic field (spin S=1/2) the same formalism holds, 
but the gyromagnetic factor .gamma..sub.e is equal to 
1.7576.times.10.sup.11 radian. sec.sup.-1. Tesla.sup.-1 or 657 times 
higher, owing to the much lesser mass of electron. In a hydrogen atom we 
have a nucleus with spin I=1/2 coupled to an electron with a spin of 
S=1/2. The Hamiltonian for such system is 
EQU =.gamma..sub.e hH.sub.z S.sub.z +AI.S-.gamma..sub.n hH.sub.z I.sub.z (5) 
where A is a measure of coupling between the two spins. This expression is 
valid for the electron in the ground i.e. non-excited state. In so called 
strong field approximation i.e. when .gamma..sub.e hH.sub.z &gt;&gt;A the 
Hamiltonian becomes 
EQU =.gamma..sub.e hH.sub.z S.sub.z +AI.sub.z S.sub.z -.gamma..sub.n hH.sub.z 
I.sub.z (6) 
and the energy eigenvalues are then 
EQU E=.gamma..sub.e hH.sub.z M.sub.s +Am.sub.I.m.sub.s -.gamma..sub.n hH.sub.z 
m.sub.I m.sub.s =.+-.1/2; m.sub.I =.+-.1/2 (7) 
There are four possible transitions in such a system, which are shown in 
FIG. 2. Symbol+-means m.sub.s =+1/2, m.sub.I =-1/2 etc. 
FIG. 2 is an energy level diagram showing the allowed transitions for an 
hydrogen atom in an external magnetic field H.sub.z. 
The resonant frequencies for electronic and nuclear transitions are 
correspondingly: 
##EQU1## 
There exists an Overhauser-Pound Family of Double Resonances as described 
by Slichter in Principles of Magnetic Resonance, 2nd ed. Springer Velas, 
Berlin, 1978. In the nuclear Overhauser effect, one observes the change in 
the integrated intensity of the NMR absorption of a nuclear spin as a 
result of the concurrent saturation of another NMR resonance. 
FIG. 3 shows an energy level diagram for S=1/2 and I=1/2 showing the 
transitions being `pumped` or excited and observed transitions. W.sub.e 
and W.sub.n are nuclear and electronic relaxations. In Electron Nuclear 
Double Resonance (ENDOR) transitions 1-2 or 4-3 are pumped. In Electron 
Electron Double Resonance (ELDOR) transition 2-3 is pumped. The observed 
transition is 4-1. In the simple NMR the same transition is excited and 
its relaxation observed (4-3) or (1-2). If in addition another transition 
(e.g. 2-3 or 1-4) is excited, than the intensity of levels will be changed 
and change in intensity and apparent change in the relaxation rate will 
manifest itself in the monitored NMR transition, so if the ESR `pumping` 
generator is amplitude modulated including pulsing on and off, this 
modulation will be transferred to the NMR signal. The limiting case of 
amplitude modulation is on-off pulsing. It may be expected that if the ESR 
pumping generator is frequency modulated instead of amplitude modulated, 
and if the frequency deviation is sufficiently high, it will have the same 
effect on the NMR signal. 
There are two methods of establishing a very high frequency magnetic field 
which will satisfy conditions of ESR resonance in the principal field of 
the NMR imager. The ratio of ESR to NMR excitation frequencies which must 
be satisfied by the same principal field is in the range of 600 to 700. 
Preferably the ratio is equal to .gamma..sub.e /.gamma..sub.n =657. An 
important factor is the choice of the ESR frequency. The sensitivity of 
the NMR readout increases with the intensity of the principal field. The 
imagers with the lowest magnetic field operate around B=0.03 T which 
corresponds to the NMR frequency for protons of 1.28 MHz and to the ESR 
frequency of 839 MHz. According to published data the (1/e) penetration 
depth at this frequency is 3.1 cm in the tissues with high water content 
and 20 cm in tissues with minimal water content (Radiofrequency 
Electromagnetic fields, NCRP Report 67, Wash., 1981). Thus, it may be 
possible to reach parts of the cerebral cortex and some other superficial 
structures, by means of surface coils. It may be possible to update the 
imager at a field lower than 0.03 T to remedy the penetration 
difficulties, however, sensitivity of the present method may be 
compromised. The unknown factor is the intensity of the very high 
frequency field that can be induced in the body in vivo. For this reason 
the ESR frequency source should operate with very narrow, high amplitude 
bursts of power, so that the average power level is tolerable. 
In operation, the sample is placed inside the main magnetic field 10 and an 
RF pulse from a source 16 is applied by the coil 12 to excite to resonance 
a plurality of nuclear spins in the sample to produce an NMR signal. A 
microwave pulse from the generator 22, through the radiators 12 or 14, 
excites to resonance a plurality of electron spins in the sample. The 
modulator 26 operates to modulate the intensity of the microwave signal 
which results in the intensity of NMR signal being modulated. Typical 
modulation systems in ESR techniques are disclosed in U.S. Pat. No. 
3,100,280. The modulator 26 may utilize either amplitude or frequency 
modulation to modulate the output of the generator. The modulation of the 
NMR signal is extracted from the NMR signal which then produces an image 
representative of the local ESR and thereby, the concentration of 
paramagnetic species in the sample. Conventional computer techniques can 
be utilized to extract the modulation from the NMR signal. 
In another embodiment, paramagnetic tracers are introduced into the sample 
prior to placing the sample into the main magnetic field. Paramagnetic 
traces are introduced as contrast agents to improve the differentiation 
between tissues and also improve the detection of pathological changes. 
Paramagnetic substances shorten the proton relaxation times which result 
in signal intensity enhancement. A large variety of contrast agents have 
been suggested and tried in vivo. Of particular interest are chelates of 
gadolinium trivalent ion, nitroxides and molecular oxygen. 
An expression of the electrical activity in the nervous system is the 
propagation of the nervous impulse or action potential, which originates 
at the body of a neuron and propagates along the axon. There are two 
current loops travelling along the axon. The first corresponds to the 
depolarization currents and the second is caused by the the repolarization 
currents. FIG. 4 shows the distribution of currents in an arbitrary plane 
incorporating an axon 30. See, Barach, et al., Experiments on the Magnetic 
Field of Nerve Action Potentials, J. Appl. Phys. 51 4532-4538, 1980. The 
action potential moves from left to right. The current inside the axon is 
represented by current dipoles shown as arrows 32,34. The current outside 
the axon, shown as symmetrical loops 36, flows through the intercellular 
medium and being axially symmetrical, with an axis coinciding with that of 
the axon 30, generates an axially symmetrical magnetic field. This field 
is shown in the form of wide bands 38 encircling the axon 30. 
The magnetic field of an axon in a conducting medium has been calculated 
and measured by Wikswo. See, Wikswo, Cellular Action Currents, 
Biomagnetism, Plenum NY, 1983. A typical form of the time dependence of 
magnetic field in the vicinity of an axon transmitting an action potential 
is shown in FIG. 5. FIG. 5 shows a magnetic field waveform in the vicinity 
of an axon in conducting medium during passage of an action potential. 
Only the magnitude but not the shape changes with the radial distance from 
the axon. 
The magnitude of the magnetic field of an axon corresponding to the peak of 
the wave form is shown in FIG. 6. FIG. 6 shows the magnitude of the peak 
value of the magnetic field waveform in the vicinity of a crayfish axon. 
As the technology of producing homogeneous magnetic fields improved, the 
observed width of NMR spectral lines became reduced. Factors influencing 
the width of a NMR spectral line can be divided into two categories: 
instrumental and physical. The main instrumental factor is the homogeneity 
of the principal magnetic field within the investigated volume and its 
constancy during the period of measurement. With the best of designs 
involving superconducting magnets and elaborate shielding systems, 
uniformity of the main field across a sample volume of about 1 cm.sup.3 
can be as high as one part per billion (10.sup.-9). A similar degree of 
stability can be obtained for periods of minutes or even tens of minutes. 
If there were no other factors broadening the spectral lines the 
attainable line width would be as narrow as 10.sup.-9 on a relative scale. 
The physical factors broadening the NMR lines are many and discussions 
concerning their contributions to the overall spectral line width are 
available in the literature. The main factors are connected with 
relaxation processes: spin-lattice and spin-spin characterized by 
characteristic time constants T.sub.1 and T.sub.2 respectively. These time 
constants are indicative of the average time the nucleus retains its 
polarization and it can be shown that for tissues like grey matter of the 
brain T.sub.2 is much shorter than T.sub.1 and thus provides a major 
contribution to the line width .DELTA.f. 
EQU .DELTA.f=1/(.pi.T.sub.2) (9) 
For a T.sub.2 value in the vicinity of 100 ms the line width is about 3 Hz. 
If the resonance frequency of NMR was set at 200 MHz the relative 
bandwidth is 1.6.times.10.sup.-8. From FIG. 6 it can be seen that the 
magnetic field oi the action potential travelling along the axon produces 
at distances below 0.1 mm a field approaching 10.sup.-8 T. This leads to 
the relative contribution of the field of a firing neuron in the region of 
2.times.10.sup.-9., i.e. 10% of the line width determined by T.sub.2. This 
may be a measurable contribution in a brain with neuron density of about 
10.sup.7 neurons cm.sup.-3. A similar situation exists for NMR of .sup.31 
P. However, the nucleus of .sup.31 P has a small quadrupole moment, which 
leads to some additional broadening of the resonance line. 
In operation, the apparatus of FIG. 1 is used to image a plurality of NMR 
spectral lines from the modulated NMR signal. The NMR spectral lines have 
a defined width. Thereafter, the contribution of the spectral line width 
due to the electrical activity of the brain is measured which provides 
information on the electrical activity. 
In addition, the method of detecting and measuring electrical activity of 
the brain of a human subject can be utilized in an NMR machine wherein the 
subject is placed in a spacially homogeneous main magnetic field and an RF 
pulse is applied to resonate a plurality of nuclear spins to produce an 
NMR signal. A plurality of NMR spectral lines are imaged from the NMR 
signal. The width of the spectral lines is broadened due to the discharge 
of a neuron in the brain which introduces an inhomogeneity in the main 
magnetic field. The broadening is measured and the contribution of the 
spectral line width due to the electrical activity is then determined. 
This provides a measurement of the neuron discharge current flux in the 
brain. 
While several embodiments of the subject invention have been described and 
illustrated, it is obvious that various changes and modifications can be 
made therein without departing from the spirit of the present invention 
which should be limited only by the scope of the appended claims.