Vivo P-31 NMR Imaging of Phosphorus Metabolites

This invention relates to non-invasive systems for obtaining medically and scientifically significant information from living bodies, and more particularly to an improved method and means for in vivo NMR imaging using phase-encoded spin echoes for obtaining one-dimensional discrimination of P-31 spectra from different parts of phantoms, muscle, and other body tissues, including brain tissue.

Phosphorus nuclear magnetic resonance (P-31 NMR) is now established as a valuable non-invasive method for investigation of the metabolic state of tissues in vivo.

Nuclear magnetic resonance (NMR) offers the opportunity of selectively examining the nature and function of nucleii of atoms attached to a variety of important biochemicals, of which phosphorus and carbon appear to be currently the most useful and are pivotal in cell metabolism as well. Nuclear mangetic resonance can be most simply described as a pulsed nuclear clock, the rate of which is sensitively dependent upon the chemical environment of the particular nucleus. For example, the atoms of phosphorus, which are attached to a series of key energy-related compounds of the body, give an appropriate signature where the important phosphate compounds in the brain, heart, kidney, liver, and skeletal tissues are the high energy compounds, adenosine triphosphate (ATP), the "energy currency" of the body, and creatine phosphate (PCr), the "short-term energy reserve" of the body, together with low-energy forms of these compounds, adenosine diphosphate (ADP) and inorganic phosphate (P.sub.i). In addition, the sugar phosphate derived from the metabolic pathway activated by glucose metabolism can also be found (F6P, DPG).

In order to realize the full potential of the method, it is important to be able to discriminate between different spatial regions of the tissue under examination. There is a definite need for a more versatile approach than has been available in the past for using NMR imaging techniques to discriminate substantially simultaneously spatially different regions of the tissue under examination, for example, for substantially simultaneously showing the P-31 spectra from different planes through the tissue.

Accordingly, a main object of the invention is to provide a novel and improved system for performing in vivo spectral imaging, in which spatial information is encoded as the phase of an RF echo and wherein it is possible to retain the spectral information needed for interpretation of the metabolic information associated with spaced slices of the tissue under examination.

A further object of the invention is to provide an improved system for performing P-31 NMR spectral imaging wherein discrete spectra can be obtained in vivo from slices of tissue of relatively small thickness.

A still further object of the invention is to provide an improved system for performing NMR spectral imaging on a specimen positioned within the bore of the magnet of an NMR spectrometer assembly and exposed to RF excitation pulses, wherein pulsed magnetic field gradients are applied to the specimen, whereby the atomic spins at each point along the gradient direction are caused to precess with different Larmor frequencies, the pulsed magnetic field gradients being incremented in strength and the RF echoes obtained thereby corresponding to regions of the specimen spaced along the gradient direction in accordance with the strengths of said gradients.

A still further object of the invention is to provide an improved non-invasive system for in vivo phosphorus imaging using phase-encoded spin echoes to obtain one-dimensional discrimination of P-31 spectra from different parts of phantoms, muscle and brain tissue, wherein the metabolic state of different spatial regions of the material under study can be discriminated and imaged, and wherein the P-31 NMR signals from different metabolites can be distinguished by chemical shift differences.

Further objects and advantages of the invention will become apparent from the following description and claims, and from the accompanying drawings, wherein:

FIG. 1 is a block diagram of a typical NMR spectrometer system for phase-encoded phosphorus imaging according to the present invention.

FIG. 2 is a longitudinal cross-sectional perspective view of the main field magnet and the associated field gradient surface coil array employed in the system of FIG. 1, showing how a live specimen is supported in the main field magnet for NMR spectral analysis.

FIG. 3 is a side elevational view of the gradient field coil assembly employed in FIG. 2.

FIG. 4 is an end elevational view of the gradient field coil assembly of FIG. 3.

FIG. 5 is an enlarged side elevational view of the specimen and supporting platform employed in FIG. 2.

FIG. 6 is a compressed timing diagram showing typical relationships of the magnetic field pulsed gradients, the excitation RF pulses, and the RF echo signals in a typical P-31 spectral imaging system, such as that shown in FIG. 1.

FIGS. 6A and 6B are diagrams to illustrate the resolution of the magnetic field strength vectors associated with the gradient coils employed in the system.

FIG. 7 shows a typical set of spectra comprising P-31 spectra obtained from the head of a live animal in which the carotid artery is occluded to form a unilateral ischemia, wherein the animal's head was placed in the homogeneous main field of the magnet and the field gradients were applied along a transverse axis aligned with the ears of the animal, using the system of FIG. 1 and FIG. 2.

Referring to the drawings, a system according to the present invention employs an arrangement basically illustrated diagrammatically in FIG. 1, comprising a hollow, longitudinally extended, horizontally positioned NMR magnet 11, for example, an Oxford Instruments 7-inch bore magnet, in association with an NMR spectrometer and computer 12, wherein the spectral frequency employed is that for P-31, namely, 24.3 MHz. The RF coil unit, shown at 13, may comprise a single Helmholtz RF coil (a two-turn split RF coil with coil separation of about 25 mm), used for RF excitation and detection in a conventional manner. One-dimensional imaging is performed using a phase-encoded spin echo method employing repeated pulse sequences shown in FIG. 6, controlled by the spectrometer unit 12. A spin echo is formed by applying a 90.degree. RF pulse 14, followed after a time period T by a 180.degree. RF pulse 15. During the time period T, which may be of the order of 20 ms, pulsed magnetic field gradients 16 are applied to the specimen (supported within the bore of hollow magnet 11 with the specimen's head located within the RF coil 13 in RF coupling relation therewith, as shown in FIG. 5). These gradients cause the P-31 spin at each point along the gradient direction (in this case along a horizontal transverse axis X (see FIG. 4), suitably oriented transversely to the specimen) to precess with a Larmor frequency which depends on the X-axis location of said point, so that at the time of application of the 180.degree. RF pulse the phase of the spin component will depend on its location along the X axis. The gradients 16 are linearly incremented in intensity in the time sequence shown in FIG. 6, so that the spins are thus "phase-encoded" with respect to the positions along the X axis and so that at the time of application of the 180.degree. RF pulses, the phase of each spin component will depend on its position along the X axis. The "null" value of the gradient, shown at 17, represents the uniform field strength value in the interior bore of magnet 11.

Referring to FIGS. 2-4, the magnetic field gradients shown in FIG. 6 are generated by two pairs of symmetrically mounted surface coils 18, 19 secured on diametrically opposite sides of a non-magnetic cylindrical supporting shell member 20 mounted in the hollow main magnet and closely fitting its inside surface, each pair of coils 18, 19 being located symmetrically with respect to the transverse vertical central X-Y plane 21, and the coils 18, 18 and 19, 19 being symmetrically located on opposite sides of the longitudinal vertical Y-Z plane. The surface coils 18, 19 subtend approximately 120.degree. around the longitudinal Z axis, as shown in FIG. 4.

The surface coils are pulsed via a PDP 11/22 unit 22 and a current drive unit 23, under the control of the NMR spectrometer and computer stage 12, to provide timed respective incremented pulse currents flowing in the coils 18, 19 in the directions indicated in FIG. 3. The pulse currents generate respective magnetic field strength vectors which are resolved to define resultant X-distributed magnetic field strength vectors providing the gradient pulses 16 shown in FIG. 6.

This is explained as follows, referring to FIGS. 6A and 6B: Imagine a horizontal slice through the X-gradient coils; there will be four wires carrying current out of the paper (drawn) as circles) and four wires carrying it back (drawn as x symbols).

Consider the field near the center point produced by the four wires 1-4. At the center point, coils 1 and 2 produce fields as shown at the left in FIG. 6B, with a net result shown at the right in FIG. 6B.

By symmetry, the wires 3 and 4 produce an equal result in the opposite direction and there is no net field. As we move off the Z axis along the X axis, wires 1 and 2 always produce a field along the +Z direction, while wires 3 and 4 produce the opposite effect. But because the field is inversely proportional to the square of the distance from the wires, the field from wires 1 and 2 increases while that from wires 3 and 4 decreases as we approach wires 1 and 2, resulting in a net axial rightwardly-directed component. As we approach wires 3 and 4 the net axial field is leftward, nemely, reversed. Near the origin, with appropriate positions of wires, the effect is such that the resultant axial field varies linearly with the distance off the Z axis along X. The return wires have a similar, but smaller, effect in reverse.

The current pulses to the gradient coils are controlled by the PDP 11/23 unit 22 to generate recurrent trains of the equally incremented gradient pulse wave shape sequence shown in FIG. 6, comprising a series of equally decremented negative (relative to "null" value 17) diminishing-strength pulses, an intermediate "null gradient" (zero gradient) stage 17, and a series of positive, equally incremented increasing-strength gradient pulses relative to the null value. The gradient pulses are spaced by a sufficient time interval to allow echo collection, for example, about 4 seconds.

Thus, the echo signals, shown at 24 in FIG. 6, are collected at "zero gradient", so that under these conditions the precession frequency depends only on the chemical shift. A series of N different echoes may be collected, corresponding to N equally incremented "phase encoding" X values. For example FIG. 6 shows 13 values, thereby providing 13 equally spaced X values for a complete sequence of N echoes. The complete sequence of N echoes may be repeated a number of times for signal averaging.

The averaged echoes 24 are subjected by the computer system associated with the spectrometer unit 12 to a two-dimensional Fourier transformation to yield respective spectra (shown, for example, at 25 in FIG. 7) as functions of position along the X axis. The spatial resolution and total field of view are related to the number and values of the field gradients by the characteristics of the digital, discrete Fourier transforms in a manner similar to that in which the spectral resolution and sweep width are related to the temporal sampling of the free induction decays (FID) or echoes.

The PDP 11/23 unit 22 is a conventional computer which is specifically programmed to control the time, duration and amplitudes of the currents furnished to the gradient coils 18, 19 via the current drive unit 23. The programmed computer 22 is enabled by the computer system forming part of the NMR spectrometer unit 12.

From FIG. 6 it will be seen that the echoes 24 are collected sequentially in the time intervals (about 4 seconds) between the successive gradient pulses 16, namely, between the 180.degree. RF pulses 15 and the next 90.degree. excitation pulses 14. The respective echoes 24 are recorded for a substantial number of repeated sequences of N echoes, and are then averaged. The averaged echoes are subjected to a two-dimensional Fourier transformation to yield the respective spectra 25 as functions of position along the X axis. The respective spectra are then stored and subsequently may be simultaneously displayed in the manner illustrated in FIG. 7, namely, as functions of specific positions along the X axis, corresponding to slices.

In the typical experimental example illustrated in FIGS. 2, 5 and 7, to discriminate between the right and left hemispheres of a gerbil head, one carotid artery was occluded and the gerbil was supportingly positioned on a platform element 26 having opposite depending, semicircular, resilient transverse leg structures 27, 27, shaped to adjustably fit within the shell member 20. The gerbil's head was received in the NMR probe coil assembly 13 in the manner illustrated in FIG. 5, and the platform was adjusted to place the animal's ears and the probe coil 13 substantially in the X-Y plane 21. In this experimental model of stroke, the animal was first rendered hypoxic by a diminution of inspired oxygen, and one hemisphere of the animals's brain was rendered more hypoxic than the other by unilateral occlusion of the common carotid artery. As shown in FIG. 7, spectra 25 were obtained for 9 gradient values, for the region transversely relative to the longitudinal axis of main magnet 11, corresponding to the location of the gerbil's head (9 echoes were collected, with an average of 100 scans on each echo, to give a spatial resolution of 5.8 mm). The overall experimental run time was about one hour. One can clearly discern the differences between the right and left halves of the gerbil head in FIG. 7 by measuring the relative amounts of P.sub.i and PCr in the series of spectra 25.

The experimental results above described demonstrate the practicality of performing in vivo P-31 NMR spectral imaging on a wide range of living tissue specimens, employing the above-described method. By using the above-described imaging technique, in which spatial information is encoded as the phase of an echo, it is possible to retain the spectral information needed for slice-by-slice interpretation of the phosphate metabolic information. The experimental data also demonstrates that discrete spectra can be obtained in vivo from slices only a few mm thick.

The above-described method can be readily employed to study the phosphate metabolic information for the human head and for other living parts of a human body or of a living animal, by using suitably scaled-up equipment conformable with the linear dimensions of the specimens to be studied.

The technique of spatially resolving metabolic spectra according to the present invention may be extended to obtain two-dimensional slice information for living specimens, or even three-dimensional information; the technique may also be extended to nucleii other than phosphorus, such as F-19, C-13, Na-23, etc. Also, gradient pulse time sequences other than the specific pulse time sequence above described, and illustrated in FIG. 6, may be employed within the spirit of the present invention.

Various modifications within the spirit of the present invention may occur to those skilled in the art. It is intended that such modifications should be comprehended within the meaning and range of equivalents of the disclosed embodiment.