Object of this Patent
This invention introduces a new category of pulse sequences which can be used as a magnetization-preparation preamble to any standard data-acquisition sequence in all branches of Nuclear Magnetic Resonance (NMR).
In the broadest terms, the purpose of the invention is to assist a standard NMR/MRI investigation of a physically complex samples by separating from each other signals originating from sample components with different values of their longitudinal relaxation times T1.
Essence of the invention
The central part of this patent is an RF pulse sequence preamble nicknamed PERFIDI (Parametrically Enabled Relaxation Filters with Double and multiple Inversion).
The nickname indicates that the pulse-sequence preamble operates as a filter, extracting signals originating only from sample components whose longitudinal relaxation times T1 lay within a given interval of values. Being defined parametrically (with delays between pulses acting as settable parameters), the functional shape of the filter can be to a large extent controlled by the operator of the NMR/MRI instrument.
The PERFIDI method uses a specially timed and cycled series of RF pulses, all of which are exclusively of the magnetization-inversion type (180° pulses, composite inversion pulses, etc). The latter fact gives the method a considerable immunity from artifacts which otherwise often arise from the presence of hard-to-control transverse magnetization components. In addition, any remnants of perpendicular components (for example those due to RF pulse imperfections) are removed by suitable phase cycles or by homogeneity spoiling field-gradient pulses.
Unlike multiple-inversion relaxation (MIR) methods tried so far, PERFIDI does not pursue the goal of suppressing signals from sample components with one or more particular T1 values. We consider such an approach hopelessly inefficient since, in addition to zeroing one or two signal components, it also drastically attenuates all the others.
Instead, PERFIDI separates the signals by creating pass-through intervals of T1 values. It turns out that, in this way, one can create T1 relaxation filters of high-pass, low-pass and band-pass varieties with surprisingly high signal yields for the desired (passed-through) signal components. This is reminiscent of a similar situation in electronics where band-pass filters and narrow stop filters both exist but are used for completely different purposes (the former to separate signals, the latter to stop a disturbance with a characteristic frequency).
As an example, the Figure on the right shows the signal yield (vertical axis) for a series of four high-pass 4-pulse PERFIDI filters with respect to the relaxation rate r = 1/T1 (horizontal axis). The quite sharp discriminating power of the filters is evident. In this case, moreover, the individual filters differ from each other only by a scaling factor of their timing parameters.
Another substantial difference between the PERFIDI and MIR approaches is the possibility to use the free timing parameters to move the location of the filter band along the T1 scale. MIR approaches are designed to exactly null the signal from a given sample component (such as fat in MRI) so that their action is constricted by that component's T1 value. On the opposite, when using PERFIDI it definitely makes sense to carry out multiple acquisitions with different settings of the T1 "cutoff threshold", obtaining each time a qualitatively different MR spectrum or image.
Synergy with standard NMR and MRI techniques
The PERFIDI sequence is a preamble whose task it is to prepare the sample magnetization in a way which expresses the desired filter function. Immediately thereafter, one is free to apply almost any standard NMR/MRI data acquisition technique, thus combining the T1 discriminating power of PERFIDI with whatever are the other final goals of the investigation.
Essentially all NMR techniques using a static magnetic field B0 can be modified by adding the PERFIDI preamble. This includes in their integrity all techniques of MR Imaging, of High-Resolution NMR Spectroscopy and of static-field NMR Relaxometry (the only NMR technique in which the applicability of PERFIDI appears limited is Field-Cycling Relaxometry where sample magnetization is prepared by switching ON/OFF the main field, rather than by RF pulses).
In many cases it may be possible to implement PERFIDI on existing NMR instruments with little or no hardware modifications. In such cases, sequences containing PERFIDI simply need to be programmed according to the descriptions provided in the patent. In some cases it may be necessary to modify also post-acquisition data-evaluation procedures, again according to the indications contained in the patent.
It is important to understand that the invention is a pure NMR method, in the sense that it does not rely on any physical or chemical modification of the studied system such as injection of a contrast agent. Not only is it completely non-invasive but, as explained in the patent, it can be exploited to reduce the required amounts of contrast agents in techniques which rely on them.
Types of systems best suited to apply the invention
Since PERFIDI is an experimental filter procedure designed to separate among themselves sample components with different T1 values, its application presumes that the investigated sample does indeed contain components with different T1's (otherwise, there would be no point in using it). Intended as a tool, PERFIDI is therefore going to be most appreciated by those who study complex systems with a distribution of relaxation times.
An example par excellence of a complex system is of course a living body and its various tissues. This indicates in-vivo imaging and spectroscopy as well as in-vitro analyses of biological specimens (tissues, body liquids, foodstuffs, etc).
Another large application area is NMR investigation of real materials such as polymers and rubbers, especially after being subjected to wear, of porous materials totally or partially saturated with liquids (such as water and/or oil in rocks and sands), etc.
Applications to MR Imaging
Most MRI applications regard eminently complex 'systems', such as human bodies. Consequently, one appreciates the conceptual fact that MR can offer qualitatively different images of the same object simply by using, even within the same session, different pulse sequences and/or their setting.
The PERFIDI relaxation-filter preamble enhances the desired capability to generate qualitatively different images of the same region of a studied object according to the selected range of relaxation times of the components which contribute to the formation of the image contrast.
PERFIDI are also likely to have an impact on the use of contrast agents in MRI. By boosting T1 differences in MRI images, PERFIDI indirectly enhance the effects of contrast agents. The latter can be easily maximized by exploiting and optimizing the sloping sections of the filter curves. One therefore expects that the application of PERFIDI in contrast agent studies will reduce the required amounts of the agents. This is extremely desirable since the introduction of a contrast agent into a human body is an invasive and potentially hazardous act.
Applications to NMR Spectroscopy
Modern NMR Spectrometers can acquire many different types of 1D, 2D and 3D NMR spectra which are used for chemical and stereo-chemical analysis of dissolved molecules and their mixtures. Using the PERFIDI preamble, all types of NMR spectra can be subject to an additional editing according to selected bands of T1 values of individual sample components and/or molecular fragments.
This is of great importance in the analysis of complex mixtures, especially those containing large molecules (eminent examples are protein solutions and biological fluids, such as blood plasma, cytoplasm, urine, etc).
In such mixtures, the investigator faces massive overlap of spectral bands which presents a severe impediment to the analysis of the spectra. Since these are the very same cases in which one expects also the presence of many components with significantly different T1 values, the application of PERFIDI opens the possibility to acquire a number of distinct NMR spectra, each containing the spectral lines of just those components whose T1 values fall into a particular band. The final result is spreading of the NMR spectrum along a new T1 dimension and thus a dramatic decrease of the overlap between different spectral features.
Applications to NMR Relaxometry
Initially, NMR relaxometry was just the art of measuring the NMR relaxation rates of nuclides present in a sample. Today, the point of view has considerably shifted due to the fact that many applications of NMR relaxometry regard complex systems with a nearly continuous distribution of relaxation rates. For example, this is certainly the case when studying biological tissues, bones, foodstuffs, porous materials and rocks soaked with fluids, etc (all fields where NMR relaxometry is acquiring a great practical importance).
In these cases the goal of the measurement is no longer a single T1 value but a curve describing the continuous distribution of T1 values in the sample. The main obstacle in this kind of assays is again the fact that signals from the individual sample components add together and form a unique magnetization decay curve whose analysis in terms of a distribution of T21's (the so-called inverse Laplace transform) turns out to be mathematically quite difficult and, in the present of experimental noise, numerically unstable.
The PERFIDI relaxation filters permit to remove the singularity of the Laplace kernel and thus:
(a) greatly reduce the effect of experimental noise on the measured T1 distribution curves and
(b) enhance the capability of the method to resolve sharp distribution-curves features.