There are seven scientificwork packages associated with this project:
Work Package 3 (Theory, Modelling, Testing and Validation)
Work Package 4 (Magnetic Field Measurement and Environmental Field Compensation)
Work Package 5 (Magnetic Field Stabilisation in FFC-NMR and FFC-MRI)
Work Package 6 (Magnet Power Supply Stabilisation)
Work Package 7 (FFC-MRI and FFC-NMR Methods Optimisation)
Work Package 8 (FFC Contrast Agent Design, Testing and Validation)
Work Package 9 (Proof of Concepts Testing of FFC Methods)
Decomposition of non-exponential relaxation processes
Theoretical description of relaxation at low field
Advance theoretical treatment of quadrupole effects
Comprehensive theory of relaxation and tests for model systems
Validation of the relaxation theory for tissues
Efficiency of contrast agents at low field
Time-saving experimental and data analysis protocols
This work package regroups world-leading research centres that focus on similar aspects of the theory of spin relaxation for FFC-NMR in an effort to build the theoretical framework and the corresponding analytic tools for the treatment of FFC-NMR and FFC-MRI data.
Over the years, P6 and P3a have been developing complementary and alternative theories to describe many different limiting situations addressed in WP3. In particular, both groups have considered systems where relaxation is likely beyond its conventional perturbation regime because of slow molecular dynamics and/or strong spin interactions (which are often locally anisotropic due to complex molecular arrangement and they have overcome the problem in the case of paramagnetic MRI contrast agents. P6 has also extended this approach to quadrupolar peaks and have developed its expertise in this area.
Much of the difficulty in the process of modelling living tissues arises from the dynamical and structural complexity of biological systems. WP3 includes the rich experience of P7 in tissue-mimicking systems and their modelling , which will foster the intermediate theoretical developments of P6 and P3a before they consider the challenging real systems provided by P6 and P2, as well as the world-leading expertise of P5 in contrast agents in biological tissues, which will provide unique insights in the molecular dynamics of specific relaxation mechanisms of interest and will greatly facilitate the development of the corresponding theory (in particular in water transport through membranes).
WP3 consists involves developing the theory of relaxation, which will be systematically cross-checked to produce reliable theoretical and analytical tools.
Deliverables comprise theoretical descriptions and models of interactions between nuclear spins and their surroundings, which give rise to the relaxation phenomena measured in FFC-NMR and FFC-MRI. Deliverables also include numerical tools and software to analyse relaxometry data in order to detect and quantify biomarker parameters in tissues.
Work Package 4
The objectives of this work package are i) to compensate static and time varying surrounding magnetic fields in the vicinity of both systems (NMR in Grenoble, and MRI in Aberdeen), and ii) to ensure the generation of any relaxation field for ultralow FFC-NMR/MRI measurements, in the range [2µT - 1mT].
This work can be split into the following key steps :
• Roll-out magnetic sensors for measuring the magnetic environments of both the FFC-NMR relaxometer (Grenoble) and the FFC-MRI scanner (Aberdeen)
• Develop mathematical models for the sources of the magnetic perturbations (static and time-varying)
• Based on these models, design coils aimed at compensating DC & AC perturbative fields, and at creating ultra- and very-low fields (ranging from 2µT to 1 mT)
• Develop and implement the coils in Grenoble and Aberdeen
• Implement an automatic compensation software for both the FFC-NMR and FFC-MRI systems
At very-low fields, FFC measurements can potentially exploit inter- and intra-molecular magnetic interactions which vary slowly with time and are highly sensitive to disease state. However, this can only be done if any contaminating magnetic fields can be measured and cancelled out and if the systems allow the generation of controlled ultra-low fields. The current magnetic subsystems embedded in the FCC-NMR located in Grenoble, and in the FCC-MRI developed by UNIABDN in Aberdeen do not currently allow a sufficient compensation of the perturbation fields to meet this objective.
WP4 will develop cutting-edge low-field correction systems for both systems through five tasks using an iterative approach. It will start with preliminary compensation of the DC perturbation fields which will then be extended to AC perturbation fields up to 500 Hz, first at small scale on the FFC-NMR relaxometer and then on a larger scale on the FFC-MRI scanner.
Deliverables include measurements of the static and time-varying magnetic fields in the laboratories of Grenoble and Aberden, together with analytical models of those fields, and methods to correct for the environmental fields using existing coils. An optimised magnetic field sensor will be demonstrated, as will designs for low-field correction coils. An automated correction system for environmental magnetic fields will be demonstrated.
The methods of FFC-MRI require the application of non-conventional MRI magnets and control systems.
In FFC-NMR relaxometry and FFC-MRI the magnetic field must vary rapidly during the time of the experiment. At the same time the stability of the magnetic field during the acquisition of an image and/or the diagnostic experiment at ultra-low fields must be comparable with the stability of conventional fixed field clinical MR scanners.
The magnets adopted for FFC-NMR and FFC-MRI are resistive air-core low-inductance solenoids that generate a magnetic field proportional to the electric current provided. Their geometry and distribution of windings is optimised to get the best field uniformity in the detection volume and are controlled by power supplies using a current command. Therefore both the control and the stabilisation of the magnetic field currently used in FFC methods rely on an indirect approach based on the capability to detect and control the current flowing in the magnet. The experience of P1 shows that this indirect method used for the current control and time stabilisation of the magnetic field, together with the precision of the commercially available current sensors, are not sufficient to guarantee the field stability necessary to acquire a FFC-MRI image. The lack of field stability on also impacts on the FFC-NMR performances and prevents resonant experimentation over a time scale of more than several hundreds of microseconds, which prevents the development of cutting-edge pulse sequence technologies such as magnetisation preservation technique using singlet states.
The objective of this work package is to develop new approaches and technologies based on new design concepts to overcome the limits of the currently available technology for the stabilisation and control of the magnetic field for Fast Field Cycling techniques. This WP does not include the developments made on the power amplifiers, which have been regrouped in WP6 led by P9 as they have expertise in that matter and the work load is important.
Deliverables will include a survey of magnetic field measuring technology, suitable for measuring small fluctations in high magnetic fields; from this a sensor type will be chosen and adapted for use in FFC-NMR relaxometry. In order to combine a range of feedback methods for field stability optimisation, a software package for the simulation of such a system will be demonstrated. Its results will be used in a prototype high-field stabilised FFC-NMR relaxometer. Finally, upgraded FFC-NMR relaxometers will be demonstrated.
Work Package 6
Power amplifiers are critical parts of FFC systems. They generate the electric current that circulates in the coil windings to generate the magnetic field and any fluctuation of the current affects directly the quality of the results. Currently available (even state-of-the-art) amplifiers are known to be too unstable to produce clinical-grade images on the FFC-MRI scanner at University Aberdeen’s pilot FFC-MRI system, and are detrimental to FFC-NMR experimentation that requires long phase coherence time.
WP6 focuses on the development of high current and high stability amplifiers that will go beyond present technology. The work will be led by IECO and will greatly benefit from their proven expertise in the domain. There already is a strong collaboration between University of Aberdeen and IECO so that many aspect of the improvement process have already been identified. The tasks listed here are therefore strongly supported by previous experimentation at site in Aberdeen.
This task will focus on improving the current FFC-MRI system at site in Aberdeen. So far no company has succeeded in developing a high current bipolar magnet power supply with significantly better than 10 ppm stability. For the development of such high power and high stability bipolar magnet power supply, the project foresees the development of new kind of amplifier, improvements in current sensor technology or improvement in the control mechanism of the amplifier system. In addition to the development work, the task also includes implementation of the developments in the system in Aberdeen and stability tests after integration.
Reliable measurement to measure amplifier’s real stability at the ppm level is one of the challenges when working in extreme strict stability regimes, not affected by magnet’s possible instabilities. Current stability in the magnet can be affected by several factors, mainly originating either from the power amplifiers or from coupling with other electrical systems via the magnet itself. The work package therefore also include the development of measurement tools for this purpose. This will allow measurement of the power supply’s real stability at the ppm level without being affected by the magnet’s possible instabilities.
Prototypes developed in the project will be tested Aberdeen FFC-MRI system.
The improvement made in field control will have to be monitored regularly in situ at site in Aberdeen. The final prototype versions will be developed and tested based on the testing feedback.
Fast Field Cycling is also used for NMR experiments in ultra-low field, to enable switching off the unit during the cycle.
The IDentIFY project aims to stabilise high and low fields separately since the technology required are different. This will be achieved by the use of separate polarisation coils and power supplies. However, as these coils are coupled, the noise generated from the high-field power supply will result in additional perturbations during experimentation at low fields (2 μT to 1 mT) and may become the dominant source of field instability.
In order to avoid this problem, the project contains the development of a fast high-current switch that will allow switching off the high-field system entirely for the duration of the evolution period at low field, typically tens to hundreds of milliseconds. This technology is already available from IECO on other products but will have to be adapted to the high-current configuration at Aberdeen.
Furthermore, the existing hardware of a FFC-NMR relaxometer will be modified to include the above mentioned switching functionality and such test system will be provided as a prototype for the project team in Grenoble. This will allow them to verify the concept and conduct further development needed for their project tasks.
Deliverables will include a prototype of a higher-stability, low-noise current sensor for use in magnet power supplies. Technology to measure an amplifier's stability, separately from the driven magnet coils, will be demonstrated. Other deliverables will include prototypes of small-scale (FFC-NMR) and large-scale (FFC-MRI) amplifier systems with optimised feedback control.
Optimise radiofrequency receiver coils and associated hardware for FFC-NMR and FFC-MRI;
• Develop and optimise pulse sequences for FFC-NMR relaxometry of small tissue samples;
• Develop and optimise pulse sequences to speed up FFC-MRI of tissue samples and human subjects;
• Develop data analysis tools for dispersion curves obtained from FFC-NMR and FFC-MRI;
• Develop image analysis and display tools for FFC-MRI.
Deliverables will include radiofrequency coils and receiver systems for FFC-NMR and FFC-MRI. Improved pulse sequences (control software) will be demonstrated, including speed-up methods for FFC-MRI and techniques to expand the range of measurements in FFC-NMR. A software toolbox for the display and analysis of FFC-MRI images will be demonstrated.
Evaluation by FFC-NMR of current clinically-approved MRI contrast agents to assess T1-dispersion characteristics in viable tissues at low and ultra-low fields, using perfused tissues in vitro;
• Synthesis and testing of polypeptidic structures to gain insight into determinants of QPs in tissue;
• Development and testing of manganese-containing contrast agents for tumour detection.
The search for contrast agents (CA) for FFC-MRI has to rely on systems able to cause marked effect on the T1-dispersion curve over the range of magnetic fields considered for the FFC-MRI scanner. Pilot studies were performed in the past decade in collaboration between Aberdeen and University of Torino and showed great potential in both diamagnetic and paramagnetic systems.
Deliverables will include an assessment of currently-licensed MRI contrast agents as potential contrast agents for FFC-MRI. Novel compounds will also be synthesised as potential FFC-MRI contrast agents and in vitro tests of these agents will be demonstrated.
The aim of this WP is to integrate the deliverables of the other WPs. It will also support WP3 by providing FFC-NMR dispersion data.
The objectives of the WP9 can be considered in three ways:
• To accumulate FFC-NMR relaxometry profiles of a variety of samples including test objects and tissues
• To create, optimise and validate methods and protocols for the integration of the novel FFC-NMR and FFC-MRI technologies
• To apply the validated FFC-MRI methods on volunteers and patients
The objectives of the WP9 are intimately related to the developments of the work packages WP3, WP4, WP5, WP6, WP7 and WP8. We can consider WP9 as both a database platform of relaxation dispersion profiles and a validation facility.
Deliverables will include optimised protocols for the use of FFC-NMR and FFC-MRI in the detection and diagnosis of disease. Biomarkers of disease based on changes detectable by FFC will be demonstrated, and a database of typical FFC-NMR relaxation curves obtained from tissues in a range of "target" diseases will be delivered. The most promising clinically-approved contrast agents for FFC-MRI from WP8 will be demonstrated in vivo.