US 20140285.191A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0285191 A1 Kalechofsky (43) Pub. Date: Sep. 25, 2014

(54) TECHNIQUES, SYSTEMS AND MACHINE Related U.S. Application Data SEREROGRAMS FOR MAGNETIC (60) Provisional application No. 61/802,315, filed on Mar. 15, 2013. (71) Applicant: Millikelvin Technologies LLC, Publication Classification Braintree, MA (US) (51) Int. Cl. (72) Inventor: Neil Kalechofsky, Stow, MA (US) GOIR 33/483 (2006.01) (52) U.S. Cl.

(73) Assignee: Millikelvin Technologies LLC, Sc ------GOIR 33/483 Eo Braintree, MA (US) r (57) ABSTRACT (21) Appl. No.: 14/210,389 The present disclosure provides various methods and systems for performing magnetic resonance studies. In accordance with many embodiments, image or other information of inter (22) Filed: Mar 13, 2014 est is derived from Super radiant pulses.

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TECHNIQUES, SYSTEMS AND MACHINE 0007 Fluorinated glucose, which is transported into cells READABLE PROGRAMS FOR MAGNETC via glycolysis, is a case in point. Cancer cells are known to RESONANCE have higher glycolytic rates than healthy tissue. Once in the cell, fluorinated glucose is metabolized via hexokinase to CROSS-REFERENCE TO RELATED fluorinated glucose-6-phosphate and other metabolites. The APPLICATIONS fluorinated molecules are transported out of the cell at rates much lower than the metabolites Stemming from ordinary 0001. This application claims the benefit of priority to (non-fluorinated) glucose metabolic pathways. As a result, U.S. Provisional Patent Application Ser. No. 61/802,315, the fluorinated glucose-6-phosphate can be considered filed Mar. 15, 2013. This application is also related to U.S. “trapped in the cell for extended periods of time (longer than patent application Ser. No. 13/844,446, filed Mar. 15, 2013, 1 hour). Hence the expectation is that cell masses showing which in turn claims the benefit of priority to and is a con higher than background concentrations of fluorinated glucose tinuation in part of U.S. patent application Ser. No. 13/623. can be quantitatively evaluated for likelihood of being can 759, which in turn claims the benefit of priority of and is a COUS. continuation of International Patent Application No. PCT/ 0008 PET FDG has emerged over the last 30 years as a US2012/30384, filed Mar. 23, 2012, which in turn claims the reliable technique for identifying the presence of cancerous benefit of priority to U.S. Provisional Patent Application Ser. tissue, and more recently PET FDG has been employed for No. 61/466,500, filed Mar. 23, 2011 and U.S. Provisional other diagnostic purposes, including the evaluation and man Patent Application Ser. No. 61/522,076, filed Aug. 10, 2011. agement of patients with Suspected ischemic left ventricular The disclosure of each of the aforementioned patent applica systolic dysfunction, and the evaluation and management of tions is incorporated by reference herein in its entirety. patients with certain neurological indications (such as dementia and seizure). However, the approach has the con BACKGROUND OF THE DISCLOSURE siderable drawback of subjecting the patient to a radioactive burden, allowing this method to be used only intermittently 0002 1. Field of the Disclosure and in circumstances where the dose related radiation risks 0003. The present disclosure relates to methods for detect are outweighed by the benefits of the diagnostic information ing and imaging molecules that are present in a non living yielded by the PET scan. This risk-benefit analysis must be sample or a living organism, and in particular, detecting and determined (by the treating physician and patient) to favor imaging molecules, or compositions of molecules, that are imaging, which is usually only in the case where there is present in low concentrations in the living organism. Embodi known or very high-Suspicion of significant pathology Such ments of the present disclosure employ Magnetic Resonance as after a positive identification for cancer has already been Spectroscopic Imaging (MRSI). Embodiments of the present made. In addition, the costs and risks to staff and the environ disclosure do not require, i.e., are free of the use of radioac ment when manufacturing, distributing and employing radio tive isotopes. active isotopes are high. 0004 2. Description of Related Art 0009. Because the strength of the signal emitted by the 0005 Clinical molecular imaging has the potential to radioactive isotope in FDG is large, very small doses of revolutionize current diagnostic and therapeutic practice by FDG are required for PET studies. By contrast FDG is enabling in vivo detection of molecules that are biomarkers non-radioactive and biologically identical to FDG, but for various diseases or biological processes of interest. For under clinically safe dose levels research has suggested its example, altered levels of glucose metabolism are known to key metabolite, intracellular FDG-6-phosphate, is available be associated with the presence of various cancers and other is at a very low concentrations below the threshold of detec disease states; indeed, it is detection of in vivo glucose tion by present day. MRSI methods and systems under clini metabolism that forms the basis of fludeoxyglucose F 18, also cally feasible conditions (reasonable MRI field strength and known as 2-deoxy-2-Ffluorodeoxyglucose (hereinafter reasonable clinical scan times). As a result, while FDG is “FDG”) Positron Emission Tomography (hereinafter currently useful as a diagnostic imaging agent using PET, “PET). In vivo choline detection is also under study as a F'DG has not been shown to be clinically useful as a diag method of determining tumor response to chemotherapy and nostic imaging agent using MRSI. other forms of treatment. Other molecules of interest for 0010. To date, translation of MRSI to clinical use has been cancer diagnosis/therapeutic monitoring include creatine, cit hampered by the poor signal to noise ratio (SNR) of target rate and N-acetyl aspartate. molecules at low concentrations, as in the example above, 0006 Additionally, complex constructs consisting of non and/or difficulty in obtaining spectral selectivity of target biological molecules Such as perfluorocarbon nanoparticles molecule(s). Though moderate increases to SNR are avail decorated with Surface ligands designed to specifically bind able through various engineering improvements (such as to a desired biological site have been used as biomarkers in in larger magnetic fields) none of these have the potential to Vivo imaging. The challenge to molecular imaging using enable detection of in vivo biomarkers such as those MRSI is that in vivo concentration of target molecules (both described above. endogenous and exogenous) is so Small that detection is very difficult or even impossible under clinically feasible condi SUMMARY OF THE DISCLOSURE tions (which conditions include using MRI scanners with 0011 Advantages of the present disclosure will be set reasonable field strength and reasonable time periods for the forth in and become apparent from the description that fol clinical scan of the sample). As a consequence, radioactive lows. Additional advantages of the disclosure will be realized tagging of biomarker molecules using F and other radionu and attained by the methods and systems particularly pointed clides, has been used as a source of detectable signal using in out in the written description and claims hereof, as well as Vivo PET. from the appended drawings. US 2014/0285.191 A1 Sep. 25, 2014

0012 To achieve these and other advantages and in accor zation of at least one set of nuclei within the sample or subject dance with the purpose of the disclosure, as embodied herein, and at least one nearby resonant coil to cause the magnetiza in one embodiment, the disclosure provides a method of tion of at least one set of nuclei to be rotated to a new preferred performing a magnetic resonance protocol. The method angle with respect to the background magnetic field. This has includes providing a magnetic resonance device including (i) the effect of creating a pulse of transverse magnetization that a main magnet for providing a background magnetic field may be detected and processed by the MR device. The along a first direction, (ii) at least one radio-frequency coil, method further includes adjusting at least one of i) the gain and (iii) at least one gradient coil that can be controlled to and ii) the phase of the FEC coil, either before, during the define at least one region of interest. The method further rotation of the magnetization so as to suppress, highlight, or includes introducing a sample or subject to be studied into the identify one set of nuclei within the sample or subject to the MR device, employing RF pulses to rotate the magnetization exclusion of others. The method further includes processing of at least one set of nuclei in the sample or subject, optionally the pulse resulting from rotation of the magnetization for then producing an image and/or obtaining spectroscopic spectroscopic information, either in the time domain or in the information as a result of said pulses, and then inducing Fourier Transform (frequency) domain. The method further electromagnetic feedback between the nuclear magnetization includes optionally repeating the above steps in order to of at least one set of nuclei within the sample or Subject and at improve image intensity, spectral resolution etc. The method least one nearby resonant coil to cause at least one of (i) the further includes optionally obtaining proton MR image data, vector direction of the nuclear magnetization of the at least either concurrently or sequentially with the above steps, so one set of nuclei within the sample to rotate to a desired angle that any images produced by the above method may be co with respect to the direction of the background magnetic field registered with anatomical MR data. and (ii) the precessional frequency of at least one set of nuclei 0015. In some implementations, the above methods can within the sample to shift with respect to the precessional further include processing information obtained from a plu frequency of other nuclei in the sample. rality of pulses of RF magnetization to produce at least one of 0013 The method further can include employing addi (i) an image, (ii) dynamic flow data, (iii) perfusion data, (iii) tional RF pulses and RF pulse detection schemes to obtain spectroscopic identity of chemical species, (iv) physiological signals from the sample or Subject with the at least one radio data, or (V) metabolic data. frequency coil with the purpose of making an image and/or obtaining spectroscopic data or images. The method can fur 0016. In further implementations, a coil designed to ther include repeating the above steps in order to improve amplify feedback can be employed. The coil can additionally image intensity, spectral resolution and the like. The method and optionally be made to permit manipulation of the phase can still further include obtaining proton MR image data, angle of the feedback field. This coil is referred to in this either concurrently or sequentially with the above steps, so document as a Feedback Enabled Coil (FEC). Examples of that any images produced by the above method may be co additional suitable coils can be found in U.S. Provisional registered with anatomical MR data. The method can still Patent Application Ser. No. 61/882,430, filed Sep. 25, 2013, further include employing a feedback enabled coil (FEC) and which is incorporated by reference herein in its entirety for a Supplementary Spin Reservoir (SSR), described more fully any purpose whatsoever. below, as techniques for permitting feedback of nuclear mag 0017. In further implementations, the method includes netism to occur even under clinical MRI conditions where it inserting a volume containing a plurality of molecules in the normally would not. The method further includes optionally field of view (FOV) of either the resonant coil or the FEC. obtaining proton MR image data, either concurrently or This volume, termed the Supplementary Spin Reservoir sequentially with the above steps, so that any images pro (SSR), permits the production of feedback even under rela duced by the above method may be co registered with ana tively low field conditions of clinical MRI scanners. In addi tomical MR data. tion, by selecting the molecule (or molecules) inside the SSR, 0014) To achieve these and other advantages and in accor the feedback field can be made to resonate at a desired fre dance with the purpose of the disclosure, as embodied herein, quency or set of frequencies. in one embodiment, the disclosure also provides a method of 0018. In accordance with further aspects, the disclosure performing a magnetic resonance spectroscopy protocol. The provides systems for performing a magnetic resonance pro method includes providing a magnetic resonance device tocol. The system can include a magnetic resonance device including (i) a main magnet for providing a background mag including (i) a main magnet for providing a background mag netic field along a first direction, (ii) at least one radio-fre netic field along a first direction, (ii) at least one radio-fre quency coil and (iii) at least one gradient coil that can be quency coil, and (iii) at least one gradient coil that can be controlled to define at least one region of interest. The method controlled to define at least one region of interest. The system further includes introducing a sample or Subject to be studied can further include means for defining a region of interest, into the MR device, employing RF pulses to rotate the mag means for introducing a sample or subject to be studied into netization of at least one set of nuclei in the sample or subject. the region of interest and means for inducing electromagnetic Optionally the gradient coil may be used to take signals from feedback between the nuclear magnetization of at least one a defined region of interest or signals may be obtained from set of nuclei within the sample and at least one nearby reso the entire FOV of the RF coil, as desired. The method further nant coil to cause the vector direction of the nuclear magne includes employing a feedback enabled coil (FEC) and a tization of the at least one set of nuclei to rotate to a desired Supplementary Spin Reservoir (SSR), described more fully angle with respect to the first direction of the background below, as techniques for enabling feedback of nuclear mag magnetic field to generate at least one electromagnetic pulse netism to occur even under clinical MRI conditions where it of transverse magnetization M. The method can still further normally would not. The method further includes then induc include means for detecting pulse or pulses of rf magnetiza ing electromagnetic feedback between the nuclear magneti tion with the at least one radio-frequency coil. US 2014/0285.191 A1 Sep. 25, 2014

0019. In some embodiments, at least one of (i) the at least one gradient coil that is integrated into the magnetic reso one radio frequency coil and (ii) the at least one gradient coil nance system. The computer program can include instruc can be a local coil. At least one of the at least one radio tions to operate a radio frequency coil that is a whole body frequency coil and the at least one gradient coil can be inte phased array transmit/receive coil system having a plurality grated into the magnetic resonance system. The at least one of coils that can selectively transmit and receive pulses of RF radio frequency coil can be a whole body coil. Theat least one magnetization. If desired, the computer program can include radio frequency coil can be a whole body phased array trans instructions to operate a radio frequency coil that is a local mit/receive coil system having a plurality of coils that can phased array transmit/receive coil system having a plurality selectively transmit and receive rf pulses of transverse mag of coils that can selectively transmit and receive pulses of RF netization. The at least one radio frequency coil can be a local magnetization. The computer program can similarly include phased array transmit/receive coil system having a plurality instructions to operate at least one radio frequency coil that of coils that can selectively transmit and receive rf pulses of further includes a plurality of local gradient coils for locally transverse magnetization. At least one radio frequency coil controlling the gradient magnetic field. can further include a plurality of local gradient coils for 0023. It is to be understood that the foregoing general locally controlling the gradient magnetic field. The at least description and the following detailed description are exem one gradient field coil can include a plurality of gradient field plary and are intended to provide further explanation of the coils integrated into the magnetic resonance system, as well disclosed embodiments. The accompanying drawings, which as one or more local gradient coils, if desired. are incorporated in and constitute part of this specification, 0020. The disclosure further provides processor-readable are included to illustrate and provide a further understanding computer programs stored on a tangible non-transient of the disclosed methods and systems. Together with the medium for operating a magnetic resonance protocol on a description, the drawings serve to explain principles of the magnetic resonance device including, for example, (i) a main disclosure. magnet for providing a background magnetic field along a first direction, (ii) at least one radio-frequency coil, and (iii) at BRIEF DESCRIPTION OF THE DRAWINGS least one gradient coil that can be controlled to define at least one region of interest. The program can include instructions 0024 FIG. 1 illustrates a simulated SR pulse resulting to facilitate definition of a region of interest, instructions for from inverting the magnetization of a single ensemble of inducing electromagnetic feedback between the nuclear mag nuclei in accordance with the disclosure. netization of at least one set of nuclei within the sample and at (0025 FIG. 2 depicts a subject inside a Feedback Enabled least one nearby resonant coil to cause the vector direction of Coil (FEC) with an Supplementary Spin reservoir (SSR) the nuclear magnetization of the at least one set of nuclei to located nearby and inside the Field of View (FOV) of the same rotate to a desired angle with respect to the first direction of FEC. the background magnetic field to generate at least one elec 0026 FIG. 3 illustrates a Simulation of the effect of SR tromagnetic pulse of transverse magnetization M, and conditions MZ, Mxy dynamics for two resonances 10 ppm instructions to facilitate processing signals received arising apart. Both resonances start completely inverted with MZ=- from the pulse of transverse magnetization with the at least Mz, Mzi--Mz and Mxy=0. Turning on SR conditions one radio-frequency coil. centered on resonance 1 causes it to rapidly return to equilib 0021. The computer program can further include instruc rium with its Mxy passing through 90 degrees at time t-20 tions for processing information obtained from a plurality of msec. Resonance 2 remains almost completely inverted, with pulses of transverse magnetization to produce at least one of only a very small amount of transverse magnetization gener (i) an image, (ii) dynamic flow data, (iii) perfusion data, (iii) ated. spectroscopic identity of chemical species, (iv) physiological 0027 FIG. 4A depicts an example of circuitry of a feed data, and (V) metabolic data. The program can further include back enabled coil (“FEC’), wherein the phase angle of the instructions to induce electromagnetic feedback by Substan feedback field can be adjusted, either manually or via com tially eliminating the presence of a gradient magnetic field in puter control, by adjusting a phase shifter. Gain of the field the at least one region of interest by controlling the at least one can be manipulated by changing the attenuator. FIG. 4B gradient coil. The region of interest can include at least one depicts an example of a prototype FEC electronics box. Voxel, and the program can include instructions to cause theat 0028 FIG.5 shows the result of a FourierTransform of the least one gradient coil to apply a magnetic field gradient in at SR pulse resulting from inversion of a simulated sample least one of three mutually orthogonal directions. The pro containing equal amounts of two resonances labeled 1 and 2 gram can include instructions to induce electromagnetic feed that are 10 ppm apart. In a standard NMR protocol, the peaks back at least in part by selectively tuning the at least onerf coil would be equal in height as the simulation sets equal amounts to a predetermined resonant frequency. The program can of resonances 1 and 2 in the “sample'. The ratio of the peak similarly include instructions to cause the system to selec heights in the data shown is ~31. As can be seen, resonance 1 tively and controllably apply a RF pulse to the sample in order has been highlighted and resonance 2 has been Suppressed. to at least partially invert the nuclear magnetization of the at The data shown is taken only from the “sample” and does not least one set of nuclei prior to inducing the electromagnetic include any signal from the simulated SSR which was set to feedback. contain a large amount of resonance 1. The “y” axis is in 0022. In some implementations, the computer program arbitrary units and the 'x' axis in frequency units. can include instructions to cause the magnetic resonance 0029 FIG. 6 depicts aspects of an exemplary MR imaging system to operate at least one radio frequency coil and at least system in accordance with the disclosure. one gradient coil that is a local coil. The computer program 0030 FIG. 7 depicts aspects of an exemplary computer can include instructions to cause the magnetic resonance system in accordance with the disclosure for operating a system to operate at least one radio frequency coil and at least magnetic resonance system. US 2014/0285.191 A1 Sep. 25, 2014

0031 FIG. 8 is an example of a feedback system known in -continued the art. (inP = F *Im!i Be7 – 11 T. 0032 FIG.9 is an example of a feedback system for a FEC cit i coil provided in accordance with the disclosure. 0033 FIGS. 10 A-C are depictions of a FEC coil and Wherein Re and Im refer to the real and imaginary parts. Supporting hardware provided in accordance with the disclo 0039. Adding Feedback: SUC. 0040. Now feedback may be added, so that: 0034 FIG. 11 depicts a further example of a feedback system for a FEC coil provided in accordance with the dis B=|Belm, =Bme'“ 5) closure. then from equations sal: DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS an = fBm'sino2: - (m. - M.)/T, 6 0035 Reference will now be made in detail to the present preferred embodiments of the disclosure, examples of which (b T -(c) + y B.) + y Bncosa are illustrated in the accompanying drawings. The methods (in and corresponding steps of the disclosed embodiments will mdi -yf5msina - 1 (T2 be described in conjunction with the detailed description of the system. 0041. Note that the second equationC with cos C=0, Sug9. Mathematical Description of Superradiance: gests that the rf field frequency is locked to B. To see this, solve for cp. 0036. The equation of motion of the nuclear magnetiza tion in an MR experiment in a homogenous field is (i = -(c) + y B.)t + ycosandt if cosa = 0,

.. M netteti met Yzi

-- wherein M is the nuclear magnetization, B are the magnetic fields, and R is the relaxation matrix. B{ mere 0037 Transforming to a reference frame rotating with the rf field at frequency () with: with the it signs in the bracket corresponding to sin C. t1 and ()=-yB. Thetfactor for Bindicates that the riffield must be phase shifted +90° with respect to the magnetization 0042. If we write Yfm sin C.T. where t is known as the “superradiant time it is clear from Equation 6 that where gives the Bloch equations in the rotating frame of the riffield: dm/dt=0 is where t-T. This also defines the ambient con ditions for Superradiance to occur, ie where tsT2 the dynamics of the magnetization are dominated by Superradi an 3) = jy(m. Bi- - in B1) f2 - (n - M)f T ance rather than “ordinary” relaxation. 0043. Differential Equation and Solution; an cit = f(a) + y B.)miyn. B - m (T2 0044) A differential equation may be developed from Equation. First make a substitution for dim/dt to obtain: Wherein T is the constant of exponential relaxation of the longitudinal (Z) magnetization and T is the exponential con clindtd (in -yp3sina (yf5msina2a: - (m. - M)ff T)T stant of relaxation of the transverse magnetization. 0038. Defining m=me'' will allow a separation of the Bloch equations into magnitude and phase for the transverse A solution may be obtained for a Sufficiently long T, thus magnetization. d dim as 2 (7) dim, dem dó (in 4 clindt -(yBsinan) -cit = cit = time"+ imp" Y. + e”,tip Fi(a) + y B.)e"-- m + iym. B - emf-- T2 tJ,dó t,dim - Solution form is given by usech(LLYB sin C.(t-to)) where Land to are constants to be determined. Verify: i(a) + y B)+iyn. netic - 1 f T d dusech?ypusina ( - to )) di pusech(yf3usina (f - to))dt

US 2014/0285.191 A1 Sep. 25, 2014

0050. Applicant has discovered that implications of the SR condition are: (t 9 sina 0051 1) in SR conditions the nuclear magnetization of even very low concentration nuclei can be returned to equilibrium very rapidly, much faster than “normal T Thus the frequency can change as the phase is adjusted. (i.e., what time would be required for return to equilib rium in non SR conditions), with the time of return being Summary governed by to which in turn can be selected by adjust ing the settings of the feedback enabled coil and/or the 0047 Under SR conditions (tsT2) the equation of characteristics of the molecules in the SSR. motion of the magnetization for the longitudinal and trans 0.052 2) Nuclei with different precessional frequencies verse nuclear magnetizations are: and/or different Ts in the FOV of the FEC can be distinguished from one another because they will have different to and tos. For example this allows the mag netic vector of one set of nuclei to be rotated to a pre This produces a pulse of magnetization which peaks at time to ferred angle exclusive of other nuclei in the FOV. 0.053 3) Adjusting the phase and/or gain of the feed (FIG. 1): back enabled coil can also be used, either separately, together, or in conjunction with other processes, to Sup R - R. E m(0) 19 press or highlight signal from selected resonances pref O erentially over others. This allows unwanted resonances to In - R (Ra m(0)M- rsech."R M. l to be Suppressed, for example. It also allows identifica - + - {+} t T M tion of the presence and quantity target molecules. 0054 Exemplary MRI Scanner Systemization 0055 An exemplary magnetic resonance system is The phase of the transverse magnetization depicted in FIG. 4, and includes a plurality of primary mag netic coils 10 that generate a uniform, temporally constant magnetic field Bo along a longitudinal or Z-axis of a central (tanh(1-1)/r)/t-11 T) 20 bore 12 of the device. In a preferred superconducting embodi sina ment, the primary magnet coils are supported by a former 14 and received in a toroidal helium vessel or can 16. The vessel is filled with helium to maintain the primary magnet coils at Superconducting temperatures. The can is Surrounded by a m(t) = Mosech(it - i)f R) series of cold shields 18 which are supported in a vacuum lity":0 Dewar 20. Of course, annular resistive magnets, C-magnets, and the like are also contemplated. l,o -= 1 it -m(0) | = RSech'' M 0056. A whole body gradient coil assembly 30 includes X, y, and Z-coils mounted along the bore 12 for generating gra dient magnetic fields, Gx, Gy, and GZ. Preferably, the gradi ent coil assembly is a self-shielded gradient coil that includes primary X, y, and Z-coil assemblies 32 potted in a dielectric former and secondary X, y, and Z-coil assemblies 34 that are Supported on a bore defining cylinder of the vacuum Dewar Implications of the Superradiant State Equations of Motion: 20. A whole body radio frequency coil 36 can be mounted inside the gradient coil assembly 30. A whole body radio 0048 Under appropriate conditions, the nuclear magne frequency shield 38, e.g., copper mesh, can be mounted tism from one or more molecules in a sample or subject between the whole body RF coil 36 and the gradient coil contained in one or more resonant coils can be made to assembly 30. If desired, an insertable radio frequency coil 40 feedback upon itself. Under such conditions we describe can be removably mounted in the bore in an examination these molecule(s) as being in the “superradiant (SR) condi region defined around an isocenter of the magnet 10. In the tion'. The SR condition is defined as being where tsT2. embodiment of FIG. 2, the insertable radio frequency coil is Clinical MR machines cannot normally produce tsT2 con ahead and neck coil for imaging one or both of patient's head ditions. and neck, but other extremity coils can be provided. Such as 0049. This disclosure teaches, in addition to other teach back coils for imaging the spine, knee coils, shoulder coils, ings, methods and systems for achieving the SR State even for breast coils, wrist coils and the like. low concentrations of molecules in otherwise clinical condi 0057 With continuing reference to FIG. 4, an operator tions. These teachings include: use of a feedback enabled coil interface and control station is provided that includes a (FEC) to amplify, phase shift and feedback into the one or human-readable display, Such as a video monitor 52, and more RF coils the current generated by one or more operator input devices such as a keyboard 54, a mouse 56, a ensembles of nuclear spins in the target volume, the SSR, or trackball, lightpen, or the like. A computer control and recon both. that. In addition we teach the use of an additional vol struction module 58 is also provided that includes hardware ume, termed the Supplementary Spin Reservoir (SSR) which and Software for enabling the operator to select among a is inserted into the field of the MR device to ensure that one or plurality of preprogrammed magnetic resonance sequences more molecules in the MR device are in the SR condition. that are stored in a sequence control memory, if rf pulses are US 2014/0285.191 A1 Sep. 25, 2014 to be used as a part of the imaging study. A sequence control clinically safe dose levels research has suggested its key ler 60 controls gradient amplifiers 62 connected with the metabolite, intracellular FDG-6-phosphate, is available is gradient coil assembly 30 for causing the generation of the at a very low concentrations below the threshold of detection GX, Gy, and GZ gradient magnetic fields at appropriate times by disclosed MRSI methods and systems under clinically during the selected gradient sequence and a digital transmitter feasible conditions (reasonable MRI field strength and rea 64 which causes a selected one of the whole body and insert sonable clinical scan times). As a result, while FDG is able radio frequency coils to generate B radio frequency field currently useful as a diagnostic imaging agent using PET, pulses at times appropriate to the selected sequence, if rf F'DG has not been shown to be clinically useful as a diag pulses are to be used in the study. nostic imaging agent using MRSI. 0058 MR signals received by the coil 40 are demodulated 0063. To date, translation of MRSI to clinical use has been by a digital receiver 66 and stored in a data memory 68. The hampered by the poor signal to noise ratio (SNR) of target data from the data memory are reconstructed by a reconstruc molecules at low concentrations, as in the example above, tion or array processor 70 into a Volumetric image represen and/or difficulty in obtaining spectral selectivity of target tation that is stored in an image memory 72. If a phased array molecule(s). Though moderate increases to SNR are avail is used as the receiving coil assembly, the image can be able through various engineering improvements (such as reconstructed from the coil signals. A video processor 74 larger magnetic fields) none of these have the potential to under operator control converts selected portions of the volu enable detection of in vivo biomarkers such as those metric image representation into slice images, projection described above. images, perspective views, or the like as is conventional in the 0064. Applicant has devised a novel approach to address art for display on the video monitor. these limitations, based on controlled feedback-driven MR, termed “super-radiant' (SR) MRherein. The goal is to exploit Improved MRSI: SR to enable much more rapid imaging and/or increase the 0059. The challenge to molecular imaging using MRSI is spectral selectivity of targeted molecules in order to mean that in vivo concentration of target molecules is so Small that ingfully improve detection of molecules using MRSI tech detection is very difficult or impossible in clinically feasible niques, in particular molecules that would otherwise be unde conditions (which conditions include using MRI scanners tectable using standard MRSI techniques under clinically with reasonable field strength and reasonable time periods for feasible conditions. Improved spectral selectivity will enable the clinical scan of the sample). As a consequence, physicians MRSI techniques to produce more sensitive and detailed in have increasingly turned to radioactive tagging using F and vivo maps of clinically relevant molecules such as glucose, other radio-isotopes, as Source of signal for detecting target choline, lactate, and others. The method disclosed below molecules using PET. allows for the substitution of non-radioactive markers, such 0060 Fluorinated glucose, which is transported into cells as protons, F and other stable nuclei, for radioactive mark via glycolisis, is a case in point. Cancer cells are known to ers, such as For N', greatly improving the potential of have higher glycolitic rates than healthy tissue. Once in the MRSI for clinical use. This would in turn empower physi cell, fluorinated glucose is metabolized via hexokinase to cians to make diagnostic, therapeutic and Surgical decisions fluorinated glucose-6-phosphate and other metabolites. based on the MRSI data, changing the clinical cost/benefit These molecules are transported out of the cell at rates much analysis available to patients and physicians since MRSI lower than in ordinary glucose metabolism. As a result, the would not expose patients to harmful ionizing radiation asso fluorinated glucose-6-phosphate can be considered “trapped ciated with PET and/or Computed Tomography (CT). The in the cell for extended periods of time (longer than 1 hour). benefits and potential applications of MRSI as a non-radio Hence the expectation is that cell masses showing higher than active diagnostic technology are significant, and may in time background concentrations of fluorinated glucose can be include earlier screening for specific conditions, real time quantitatively evaluated for likelihood of being cancerous. monitoring of therapeutic response and other clinical appli 0061 PET FDG has emerged over the last 30 years as a cations. reliable technique for identifying the presence of cancerous 0065. The present disclosure teaches methods and sys tissue, and more recently PET FDG has been employed for tems to exploit properties of the so-called “super-radiant” other diagnostic purposes, including the evaluation and man (SR) state, defined herein, so as to either: 1) increase the agement of patients with Suspected ischemic left ventricular available signal to noise per unit time from one or more target systolic dysfunction, and the evaluation and management of nuclei and/or 2) improve distinguishability between mol patients with certain neurological indications (such as ecules for a wide variety of MRSI studies. The present dis dementia and seizure). However, the approach has the con closure further teaches methods and systems for the produc siderable drawback of subjecting the patient to a radioactive tion of the SR state for low concentrations of molecules in burden, allowing it be used only intermittently and in circum clinical MRSI conditions. stances where the benefits of the PET scan in light of an 0066. As demonstrated herein, the SR state is not one that individual patients health risks are determined (by the treat occurs under normal clinical MRSI conditions. We therefore ing physician and the patient) to outweigh the radiation bur teach the inclusion in the MR machine of a coil whose elec den, Such as after a positive identification for cancer has tronic circuitry has been configured so as to amplify any already been made. In addition, the costs and risks to staff and feedbackfield henceforth referred to as the Feedback Enabled the environment when manufacturing, distributing and Coil (FEC) and of a volume, henceforth to be referred to as the employing radioactive isotopes are high. Supplementary Spin Reservoir (SSR). The role of the SSR is 0062 Because the strength of the signal emitted by the to facilitate the production of SR conditions so that the prop radioactive isotope in FDG, is large very small doses of erties of the SR state (described below) may be more fully FDG are required for PET studies. By contrast FDG is exploited for the purposes of improving one or more MR non-radioactive and biologically identical to FDG, but at studies, imaging protocols, spectroscopic analyses, etc. In a US 2014/0285.191 A1 Sep. 25, 2014

preferred embodiment, the SSR is a container with a prede molecule or molecules that may be selected as a target biom termined concentration of one or more molecules that will be arker for imaging. In such an instance, the SSR can contain the target molecule(s) of the SRMRSI. The SSR is preferably the selected metabolite and may or may not contain the pre situated ex vivo and placed proximate to the sample to be cursor. It is also possible that the administered biomarker can imaged (for example a human or an animal) and within the serve as a target biomarker for imaging and as a precursor field of view (FOV) of one or more FECs. It may also be biomarker so that metabolites of the administered biomarker contained in its own dedicated coil/FEC arrangement. can be targeted for imaging. 0067. Applicant has discovered that: 007.9 The SSR is configured to contain an amount of the 0068. 1) In SR conditions the nuclear magnetization of biomarker suitable for inducing SR conditions for the biom even very low concentration nuclei can be returned to equi arker within the FEC. The SSR may contain one or more librium very rapidly, much faster than “normal' T (i.e., the biomarkers wherein each of the biomarkers in the SSR device time required for return to equilibrium in non-SR conditions), are present in an amount that will induce SR conditions for the with the time of return being governed by t (defined below) particular biomarkers within the FEC included in an MRSI which in turn can be selected; for example by adjusting the device. settings of the FEC and/or the characteristics of the molecules 0080 Under appropriate conditions, the nuclear magne in the SSR. tism from one or more molecules in a sample contained in one 0069. 2) Nuclei with different chemical shifts and/or dif or more FEC coils can be made to feedback upon itself. Under ferent TS in the viewing Volume of the imaging coil can be Such conditions we describe these molecule(s) as being in the distinguished from one another because they will have differ super-radiant “state' (SR). The SR state is defined as being ent to and tos (defined above). where tsT2. Clinical MR machines cannot normally pro 0070 3) By adjusting the phase of the FEC, a frequency duce the conditions necessary to produce tsT2. The present shift can be induced in one or more target nuclear magneti disclosure teaches, in addition to other teachings, methods Zations. This can also be used, either separately or in conjunc and systems for achieving the SR state even for low concen tion with other processes, to distinguish between molecules trations of molecules in otherwise clinical conditions. These with different Y and/or different Ts in the viewing volume of teachings include: use of a feedback enabled coil so that the the imaging coil. active Q of one or more FEC coils included in, or added to, an 0071. The present application also relates to methods for MR machine can be made very high, and the use of an SSR, detecting and/or imaging biomarkers in vivo in a subject for preferably ex vivo, to ensure that one or more molecules in the example a patient oran animal that employs the SR technol MR machine are in the SR state. ogy and SSR described herein. The methods can include: I0081. An embodiment of the present disclosure employs 0072 i) administering a composition including an imag the use of characteristics of the SR state described above, ing amount of at least one biomarker or precursor biomarker preferably in conjunction with an ex vivo SSR, to greatly molecule to a subject to be imaged; enhance the achievable signal to noise ratio (SNR) in an 0073 ii) positioning the subject in an MRSI device with a MRSI image or spectroscopic analysis of a biomarker or FEC and a detection coil to allow the detection of the biom molecule with intrinsically low concentration. Applicant has arker in vivo; found that the potential gain in SNR should be sufficient to 0074 iii) including an SSR containing a predetermined allow many biomarkers to be detected in vivo in particular, amount of the biomarker molecule within the FEC wherein but not exclusively, biomarkers containing one or more F the predetermined amount of the biomarker molecule in the atoms—under clinical conditions. SSR is an amount necessary to induce a SR state for the I0082 It has been previously demonstrated that, by creat biomarker; and ing SR conditions, the nuclear magnetism of the sample can 0075 iv) detecting the biomarker in the subject using be rotated very quickly back to its equilibrium position. For MSRI and obtaining an image of the desired region of the example, in the SR state it has been shown in the prior art that sample. 99.96% of equilibrium 1H magnetization in water can be 0076 v) combining data obtained as described above with returned to equilibrium in to milliseconds, far faster than the anatomical and other MRI data, obtained from the subject in “natural T1 of the water which was measured to be 865 the same session, as may be useful and known in the art, to milliseconds. form a composite database and images derived from it I0083 Being able to increase the number of scans per unit 0077. The biomarker employed in the methods of the time has a direct impact on the intensity that can be obtained present disclosure may be any clinically relevant molecule in an MRSI scan. For example, signal averaging is a well that will be tolerated by the subject and accumulate in areas, known technique for increasing image intensity wherein Suc i.e., systems, organs, tissues, or tumors, of the Subject which cessive scans are added together; the overall impact is to are of interest for imaging and/or diagnostic purposes. In one improve SNR as the square root of N where N is the number preferred embodiment, the biomarker is a molecule that con of scans. Since clinical MRSI sessions are generally limited tains at least one or more fluorine atoms. Fluorine is a pre to no more than an hour or so per sample, increasing the ferred embodiment as it is isotopically 100% 19F which has number of scans per unit time can directly improve image a relatively large gyromagnetic ratio and low background intensity. signal in vivo. I0084. Feedback in NMR systems with high field, high Q 0078. One or more biomarkers may be administered to the and high density of nuclei is well known. However, produc sample in the above method to enhance the imaging capabil tion offeedback for detection and/or imaging of biomarkers, ity. It is also envisioned that a precursor biomarker may be with typical concentrations in the micromolar range, under administered to the Subject. As used herein, the precursor clinical MRSI conditions is more challenging. In vivo biom biomarker is typically a molecule that is metabolized by the arker concentrations are generally much too low to produce subject after administration which then produces a metabolite SR conditions in a 3 T or even 7T clinical MRSI device. Even US 2014/0285.191 A1 Sep. 25, 2014

with a circuit to amplify the feedback field, the amplifier gain ject of the SR conditions. The bar or QR code could addition would have to be prohibitively high to produce feedback in ally facilitate the invoicing of patients. The labels will also biomarkers with concentrations on the micromolar scale. contain words and/or visual symbols that will allow the Even if very high gains could be employed the very low SNR operator of the MRSI device to select the appropriate SSR for of the target nuclei in such cases would make it very difficult inclusion with the particular patient scan. to produce a useful signal to feedback; noise would over (0090. Because of the variability of the in vivo levels of the whelm the signal. Also, during in vivo MRSI scans, the target or biomarker molecule(s) in a particular patient, the nucleus of interest is often some spin other than 1 H. 1H has SSR will be prepared with at least the minimum amount of the the highest gyromagnetic ratio of all nuclei and hence pro target or biomarker molecule(s) that will be required togen duces feedback most easily; attempting to cause feedback erate the SR conditions within one or more FECs. Such with ensembles of F and C' spins is more difficult. amount will be the amount required to generate the SR con 0085 Embodiments of the present disclosure employ the ditions even in the absence of any contribution from the target previously described FEC and SSR to allow the magnetiza or biomarker molecule(s) from the patient. Stated another tion of low concentration molecules, i.e., biomarkers, to feed way, the SSR will contain the amount of target or biomarker back more easily by including in the FEC of the MRSI device, molecule(s) that generate the SR conditions within the FEC preferably ex vivo to the sample, a predetermined amount of of the MRSI device when a patient is not present in the coil or one or more molecules that contribute to creating SR condi MRSI device. In embodiments of the present disclosure, the tions for that target or biomarker molecule (FIG. 2). In a minimum amount of target or biomarker molecule(s) neces preferred embodiment, the molecule(s) in the SSR are iden sary to generate the SR conditions can be determined by tical to the in Vivo target or biomarker(s) molecule. In a application of the following equation: tsT2 where t is further preferred embodiment, the concentration of the mol defined in the previous section ecule(s) in the SSR is made large enough to cause SR condi 0091. The necessary or minimum amount of target or tions for a given field and coil arrangement in the MRSI biomarker molecule(s) may be in one or more SSR devices device. In a further preferred embodiment, one or more coils present in the coil or device. Similarly, if more than one target in the MRSI device are feedback enabled to further enhance or biomarker molecule is the focus of the MRSI scan, each control over creation of SR conditions. individual target or biomarker molecule may be present in a I0086. Other embodiments include using a SSR containing separate and distinct SSR device or the combination of the one or more molecules containing nuclei whose resonances individual target or biomarker molecules may present in one are similar, if not identical, to those of the in vivo target or or more SSR devices. biomarker molecule(s). 0092. Embodiments of the present disclosure may also use 0087. The inclusion of the ex vivo SSR and the FEC allow SR to more effectively distinguish between molecules in the nuclear magnetization of one or more target or biomarker MRSI studies. molecules to be rapidly refreshed. Hence the number of 0093. From the equations above, several methods for images that can be taken per unit time is increased, leading to enhancing distinction between resonances from different higher signal averaging per unit time and higher intensity of molecules can be drawn. For example, Equation 18 above the resulting image. shows that, the time required for the magnetization of a par 0088. The SSR may comprise a storage device or con ticular molecule to flip back to 90 degrees (i.e., where t-t()) tainer for the target or biomarker molecule(s), the predeter depends on t, which in turn depends on the amount of that mined amount of the target or biomarker molecule(s) required molecule in the sample. T for a target molecule can be to generate the SR conditions and optionally a carrier for the adjusted externally; in particular, it can be made to be very target or biomarker molecule(s). The SSR storage device or different from that of any other molecule in the FOV. In one containershould be made of any suitable material that will not embodiment, this can be done by including in the FEC a SSR interfere with the operation of the MRSI device such as glass containing a large amount of the target molecule. In another or plastic and may be rigid or flexible. In embodiments of the embodiment, this can be done by adjusting the gain and/r present disclosure, the storage device is an ampoule. The phase shift of the feedback enabled coil or coils. In a preferred ampoule can be of any size, shape and Volume that can be embodiment, both inclusion of an ex vivo SSR containing the easily accommodated within the MRSI device. In some target molecule and adjustment of the FEC are used to pro embodiments the ampoules should have a volume of about 1 duce the desired SR characteristics in the target molecule. ml to 3000 ml and preferably about 1 to about 1000 ml. In 0094 For example, the magnetization of a target molecule certain embodiments, the SSR storage device or container is can be rotated to 90 degrees (with respect to the main mag sealed to prevent contamination of the contents and to prevent netic field) while those of others maintained at 180 degrees or the target or biomarker material from leaving the container. at some other angle, as seen in FIG. 3. This can facilitate The carrier, if employed, in the SSR storage device or con distinguishing between the magnetization of one ensemble of tainer may be water or another Suitable liquid Such as an nuclei and another. alcohol or organic solvent. The carrier may also be an inert 0.095 Embodiments of the present disclosure include filler Such as lactose or microcrystalline cellulose. In an alter methods (and associated systems and machine readable pro native embodiment of the present disclosure, the SSR grams for implementing the methods) for producing SR includes a tablet or capsule containing the predetermined under standard clinical MRSI conditions. For example, amount of the target or biomarker molecule(s) required to Applicant has discovered that production offeedback condi generate the SR conditions. tions can be created in vivo by introducing an ex vivo SSR, 0089. In certain embodiments, the SSR will be labeled filled with one or more target biomarker molecules, outside with a bar or QR code that can be scanned and the data sent to the patient but still inside the FEC (FIG. 2). The presence of the MRSI device to allow the MRSI device and operator to a large number of identical molecules makes it possible to know which target or biomarker molecule(s) will be the sub create SR specifically tuned to that molecule and/or a particu US 2014/0285.191 A1 Sep. 25, 2014

lar nuclei in that molecule. The feedback field created by the RF coil can be used, even receive-only coils, thus we will large number of spins in the SSR affects the identical target refer to this coil as the RF coil. The output of the preamp is molecules that are inside the sample equally. Thus, the nuclei split off and fed into a feedback circuit. After applying the of interest in the target or biomarker molecule(s) within the appropriate attenuation and phase setting/shifting, the output sample can gain the benefit of a highly accelerated return to of the feedback circuit is then fed back into the RF coil via an equilibrium even though their concentration in vivo is inductively coupled loop. In principle, the gain and phase extremely low. This allows for in vivo images/spectra to be may be any value with the potential to shorten the radiation acquired much more rapidly, increasing the SNR per unit time damping constant to any desired value. Also, as a pin diode and the image intensity. Applicant has discovered that inten Switch is employed, radiation damping can be turned on and sity gains obtained in this manner are sufficient to allow many off under system control via a pulse sequence. different molecules with intrinsically low concentrations in 0101 However, the circuit of FIG. 8 has two major short Vivo to be imaged. comings for a practical implementation of radiation damping. 0096. Applicant has further discovered that, by optionally The inductively coupled loop is loosely coupled to the RF coupling any of the above methods with a coil whose elec coil. This is necessary to prevent the output of the feedback tronic circuitry has been configured so as to amplify and/or circuit to adversely affect the tune and match of the RF coil. phase adjust any feedback field, conditions for producing SR Consequently, greater power is required by the feedback cir under a wide variety of ambient conditions can be enhanced. cuit than is necessary. To achieve Small radiation damping FIG. 4 shows one embodiment of such a coils circuitry. constants, an improvement in efficiency is necessary to Further details on such a coil can be found in U.S. Provisional reduce power requirements. A second shortcoming is that the Patent Application Ser. No. 61/733,415, filed Dec. 4, 2012, signal coming from the RF coil has two significant compo which is incorporated by reference herein in its entirety. Other nents. One component is the RF signal arising from the mag preferred embodiments can include employing RF pulse netization of the spin system. The second component is the sequences to create SR conditions for one or more target signal generated by the feedback circuit. Fortunately these nuclei of interest. two components are normally phase shifted by 90°, so that it is possible to maintain a stable mode of operation for the Further RF Coil Implementations feedback circuit. While the inefficiency of the circuit helps to 0097. SR conditions have been heretofore largely promotestability, the circuit will be sensitive to phase. With unknown in clinical MR because the requisite conditions— Sufficient gain, there is the danger of creating positive feed high magnetic field and/or high probe quality factor Q are back. not produced by commercially available MR machines 0102) Applicant has developed a circuit design which known in the art. SR conditions area more common phenom overcomes these shortcomings as shown in FIG. 9. A com enon in high field NMR studies, where they are generally ponent of the embodiment of FIG. 9 is the isolator block, considered an annoyance as their best known effect is to which causes reflected power from the RF coil to appear on broaden the spectroscopic lines of the nuclei under observa the output of this circuit but not upon the input. This block can tion. SR conditions are not desirable when one is trying to have different designs depending upon the type of RF coil resolve the identity of many different molecules in a single employed. The reflected power from the NMR coil will again sample, which is the goal typical of many NMR studies. The have two components, one component from the spin system present disclosure recognizes that SR conditions can be a and the other component will be reflected power from mis benefit when the goal is the identification and quantification match with the coil. Additional remote tuning/matching cir of a single molecule to the exclusion of others in the field of cuit(s) inside the isolator block can minimize the reflected view. By adding the notion of control, through the use of a power due to any impedance mismatches while the NMR Feedback Enabled Coil (FEC) and a Supplementary Spin signal which arises from the spin system is coupled efficiently reservoir (SSR), SR enables powerful feedback-driven MR to the receiver and feedback circuit. This can minimize the methods. undesirable component while maintaining an efficient cou 0098. As discussed elsewhere herein, SR occurs when pling to the coil. If the embodiment of the RF coil is a receive tsT2 conditions are arranged for one or more set of nuclei. only coil, then the circuit is further simplified by removing the where t1/YBlsin O.M. In this expression, B and C. are the transmitter and RF power amp from the figure. The design of magnitude and phase of the gain factor generated by a feed the isolator block can vary depending upon the type of coil back enabled coil, Y is the gyromagnetic ratio, and Mo is the used. If a surface coil (or any coil that is considered linear) is maximum value of the magnetization, which will be equal to used, then the isolator block might utilize a quadrature hybrid thermal polarization. along with a divider, i.e. Wilkinson divider and a remote 0099. As noted above, MR scanners known heretofore in matching circuit. If a quadrature or circularly polarized coil is the art are not generally capable of producing the conditions used then the isolator block may include two remote matching required for SR. In addition, they are not typically set up as circuits and one quadrature hybrid. Other designs are possible feedback-enabled devices. One way to overcome these fac for the isolator block whose primary purpose is to separate the tors is to build a coil capable of producing feedback even signal into forward power (coil transmission) and reflected under clinical MR conditions. The coil/electronics are pref power (coil reception). This design is scalable to parallel erably able to adjust the phase of the magnetization as well as imaging coil arrays. the gain of the feedback. We term such a coil a Feedback 0103 Electronic noise is amplified and fed back by the Enabled Coil (FEC). Schematics of exemplary hardware are circuit in a similar manner to the signal. If the noise is large presented below. enough it can overwhelm the desired SR effect and cause the 0100. An example of a feedback system known in the artis spins to oscillate randomly or not at all. shown in FIG. 8. In this particular case, a transmit/receive 0104. To limit the effect of noise, in a preferred embodi Surface coil is employed in a typical manner. In principle, any ment, the circuit can contain one or more RF filters; for US 2014/0285.191 A1 Sep. 25, 2014 example, bandpass filters whose passband is centered on the very wide, being only ~15 ppm. In addition, the proton reso Larmor frequency of the target nuclei. Previous RF feedback nances of choline lie very close to that of other molecules coil designs have not incorporated this feature to the knowl normally found in the same Volume of tissue such as glucose, edge of Applicant. The overall filter bandwidth is preferably NAA and others. Thus an issue is distinguishing the reso Small enough to ensure that all, or most, frequency compo nances belonging to the choline molecule from all the others nents within the bandpass of the filter do not generate positive also in the MR field of view. feedback. 0111 Applicant has found that, by including in one or 0105. Applicant has further discovered that different elec more FECs a SSR filled with one or more molecules, the tronic components have different group delays; that is, exhibit nuclear magnetization from one or more target molecules in different relationships between phase shift and frequency. It the FOV may be made to feedback upon itself. Applicant has is desirable to use components whose collective group delays further found that, in addition to the inclusion of such a SSR, are as short as practicable so that one or more phase shifters the feedback parameters such as gain and/or phase of the can be used to effectively feedback one or more target mag nuclear magnetization of those target molecule or molecules netizations. This is particularly true of filters whose group can be adjusted by amending one or more FECs in the manner delays can vary over a large range. shown in FIG. 4. 0112. As per equations 15 and 18 above, this method can Example then be used to shift either the angle of the nuclear magneti 0106. In one example, a commercially available head coil Zation from a target molecule or molecules with respect to (e.g., FIG. 10C) (e.g., single channel) for operation on a 1.5T others in the FOV, and/or shift their resonant frequency with Siemens Avanto MRI scanner (FIG. 10A) can be used, and respect to other molecules in the FOV. modified to be operated using a feedback circuit with a iso 0113. Other examples of a target or biomarker of interest lator block as set forth above with respect to FIG. 9, such as with the embodiments of the present invention are: (i) creat the illustrative embodiment depicted in FIG. 10B. A low ine (Cr), (ii) creatinine (Crn), (iii) Phosphorylcreatine (PCr), power amplifier can be used initially (~10 watts) to test the (iv) Creatine kinase (CK), (v) mitochondrial CK isoenzyme feedback circuit, to insure against positive feedback, and to (Mi-CK), (vi) Cytosolic brain-type CK isoenzyme (B-CK), obtain initial results. (vii) Cytosolic muscle-type CK isoenzyme (M-CK), (viii) 0107 Yet a further embodiment of an illustrative circuit is L-Arginine:glycine amidinotransferase (AGAT), (ix) S-ad provided in FIG. 11. The illustrated circuit provides time enosyl-L-methionine:N-guanidinoacetate methyltransferase interleaved feedback by separating the radiation damping (GAMT), (x) guanidinopropionate (GPA), (xi) guanidinobu (“RD) transmit and receive in time. This approach has the tyrate (GBA), (xii) cyclocreatine 5 1-carboxymethyl-2-imi benefit of avoiding positive feedback and thus allows larger noimidazolidine (cCr), (xiii) homocyclocreatine 5 1-car gains to be applied. This in turn can allow for shorter RD time boxyethyl-2-iminoimidazolidine (hcCr), (xiv) constants. A description of the circuit follows. The SPDT Glycocyamine 5 guanidinoacetate (Gc), (XV) taurocyamine switch is used to change between the normal MR scanner (Tc), (xvi) lombricine (L), (xvii) a N-phosphorylated forms operation and RD feedback mode. When operated in RD of a guanidino compound (PCrn, PGPA, PcCr, PhcCr, PArg, mode, the feedback time separation is achieved through the PGc, PTc, PL), (xviii) arginine kinase (ArgK), (xix) 2,4- sample and hold (S/H) and the switching of the transmit Dinitrofluorobenzene (DNFB), (XX) S-adenosyl-L-methion receive switch (T/R) via a pulse or sample train which is ine (AdoMet), (xxi) reduced glutathione (GSH), (xxii) oxi provided by the MR spectrometer. Typically the pulse train is dized glutathione (GSSG), and (xxiii) L-Ornithine:2-oxoacid on the order of 10-100 KHZ. The two mixing stages (indicated aminotransferase (OAT) or (i) citrate, (ii)acetylconenzyme A by X) are quadrature modulators to convert the feedback (acetyl CoA), (iii) oxaloacetate, (iv) aconitase, (v) pyruvate, signal to DC for the sample and hold and then to convert the (vi) NADH, (vii) FADH2, (viii) lactate and (ix) N-acetyl sample and hold output back to the Larmor frequency of the aspartate spins. The phase shifter provides the appropriate phase so that 0114. Another example of a target or biomarker of interest the RD field will drive the spins back to equilibrium. The with the embodiments of the present disclosure are fluori overall gain (G) of the loop is adjusted to reduce the effective nated glucose Such as 2-fluoro-2-deoxy-D-glucose, 3-fluoro RD time constant. 3-deoxy-D-glucose or 4-fluoro-4-deoxy-D-glucose and pref 0108. Many RF pulse sequences have been developed to erable 2-fluoro-deoxy-D-glucose. The fluorine atom in these drive equilibrium return time below T1 so that images can be molecules is F. 2-fluoro-d-deoxy-D-glucose is also known acquired more rapidly. For example, Driven Equilibrium as FDG, FDG or fludeoxyglucose. A radioactive form of Fourier Transform (DEFT) applies a restoring RF pulse after FDG, i.e., FDG is commercially available for intravenous an imaging scan to drive remaining transverse magnetization administration as a radiopharmaceutical for diagnostic pur to equilibrium. This works well in some situations but for poses in conjunction with PET. many in vivo molecules, where T1DT2, DEFT does not 0115 FDG is useful as a diagnostic agent for various work well. Other RF pulse programs have similar drawbacks. systems, especially cancer growths because cancer cells con 0109. An example of a biomarker of interest for MRSI Sume glucose at a higher rate than normal healthy cells. The imaging is choline. Choline is a biomarker used in diagnosis similarity in size between the fluorine atom and hydroxyl of many cancers, in particular brain cancer. Specifically, an moiety allow FDG to compete with glucose for transport from elevated level of choline in a suspect volume of tissue can be the patient’s blood to target tissues or cells. Therefore, compared to background choline levels in non-cancerous tis because the cancer cells consume more glucose than normal Sue to diagnose the presence of cancer. healthy cells, the cancer cells will consume more FDG than 0110. Choline is normally detected in an MRSI experi healthy cells and Subsequently have a higher concentration of ment by analysis of the proton spectrum taken from the Sus FDG than healthy cells, thereby allowing MRSI imaging in pect Volume of tissue. The proton spectrum is intrinsically not accordance with the present disclosure. FDG also is a useful US 2014/0285.191 A1 Sep. 25, 2014

diagnostic agent because it is metabolized, i.e., undergoes 0.122 v) combining data obtained as described above with phosphorylation to the monophosphate, sometimes referred anatomical and other MRI data, obtained from the subject in to as FDG-6-P or 2-fluoro-2-deoxy-D-glucose-6-phosphate. the same session, as may be useful and known in the art, to Unlike glucose that has undergone phosphorylation, FDG form a composite database and images derived from it 6-P cannot be employed in further glycolytic pathways and I0123. The composition including the fluorinated glucose has a membrane permeability that precludes diffusion from that is administered to the subject in the above described the cells back into the blood stream. Therefore FDG-6-Pgets method may be a solid or liquid. If a solid, it may be in the trapped intracellularly and becomes a biomarker formed by form a powder, Sachet, tablet or capsule. The Solid composi metabolism in the subject. tion will include the fluorinated glucose, preferably FDG, in 0116. In embodiments of the present disclosure, FDG may an amount of 50 to 1000 mg and conventional pharmaceutical be used for the characterization of pulmonary nodules, detec excipients. The pharmaceutically acceptable excipients use tion of primary cancer by cervical adenopathy, liver or bone ful in the present disclosure can be selected from the group metastases and/or characterization of pancreatic mass. In consisting of fillers, binders, lubricants, glidants, antiadher embodiments of the present disclosure, FDG may be used to ents, flavoring agents, coloring agents, disintegrants and mix stage head and neck cancers including assistance in guiding tures of thereof. A more detailed description of the acceptable biopsy, primary lung cancer, locally advanced breast cancer, pharmaceutical excipients that may be employed in the oesophogeal cancer, carcinoma of the pancreas, colorectal present disclosure can be found in Rowe et al., Handbook of cancer particularly in restaging occurrences, malignant lym Pharmaceutically Acceptable Excipients (4" ed. 2003) or the phoma and/or malignant melanoma. In embodiments of the United States Pharmacopeia 29, both of which are incorpo present disclosure, FDG may be used to monitor the thera rated herein by reference. In certain embodiments of the peutic response of head and neck cancer and/or malignant present disclosure wherein a fluorinated glucose is the target lymphoma. In embodiments of the present disclosure, FDG biomarker, the conventional pharmaceutical excipients may be used to detect recurrences of glioma with high grade employed in the composition administered to the Subject malignancy (III or IV), head and neck cancers, thyroid cancer should exclude or limit Sugar type compounds Such as lac (non-medullary), primary lung cancer, colorectal cancer, ova tose, Sucrose, maltose and fructose because these compounds rian cancer, malignant lymphoma and/or malignant mela will compete with the subjects absorption of the fluorinated noma. The FDG of the present disclosure and procedures glucose employing the same (and associated systems and machine 0.124 Examples of acceptable fillers, sometimes referred readable programs) may also be used in a diagnostic test of to as diluents, include water, Sugars, such as lactose, sucrose, viable myocardial tissues with affinity for glucose. Additional maltose, or microcrystalline cellulose; clays and mixtures applications for FDG include the diagnosis or evaluation of thereof. Preferably, the filler should be a non-sugar com certain neurological conditions such as dementia or seizure pound. where tissue with hypometabolism of glucose is an indicator 0.125 Binders that are useful in the present disclosure of pathology. include pharmaceutically acceptable Substances with cohe 0117 Embodiments of the present disclosure include sive properties. Some examples include celluloses such as methods (and associated systems and machine readable pro hydroxypropyl methycellulose, hydroxypropyl cellulose and grams) for detecting and/or imaging fluorinated glucose and/ carboxymethycellulose Sodium; polyvinylpyrrolidone; Sug or metabolites of fluorinated glucose in vivo in a sample that ars; starches and mixtures thereof. Preferably, the binder employ the SR and SSR technology described herein. These should be a non-Sugar compound embodiments comprise the steps of: 0.126 Examples of lubricants, glidants and/or antiadher 0118 i) administering a composition comprising an imag ents that may be used in the embodiments of the present ing amount of a fluorinated glucose, preferably FDG, to a disclosure include talc, magnesium Stearate, calcium Stearate, Subject; Stearic acid, hydrogenated vegetable oils, polyethylene gly 0119 ii) positioning the subject in an MRSI device with a cols, silicon dioxide and mixtures thereof. FEC and a detection coil to allow in vivo detection of the I0127. Flavoring agents that can be used in the embodi fluorinated glucose, metabolites of the fluorinated glucose, ments of the present disclosure include peppermint, spear such as FDG-6-P, or combinations of the fluorinated glucose mint, wintergreen, cinnamon, coconut, coffee, chocolate, and metabolites of the fluorinated glucose: Vanilla, menthol, licorice, anise, apricot, caramel, pineapple, 0120 iii) positioning an SSR containing a predetermined Strawberry, raspberry, grape, cherry, mixed berry, tropical amount of the fluorinated glucose, metabolites of the fluori fruits, mint and mixtures thereof. nated glucose or combinations of the fluorinated glucose and I0128 Coloring agents that may be employed in embodi metabolites of the fluorinated glucose within the FEC region ments of the present disclosure include FD&C-type dyes and wherein the predetermined amount of the fluorinated glucose, lakes, fruit and vegetable extracts, titanium dioxide and mix metabolites of the fluorinated glucose or combinations of the tures thereof. fluorinated glucose and metabolites of the fluorinated glucose I0129. Examples of disintegrating agents that can be used in the SSR is an amount necessary to induce a SR state for the in embodiments of the present disclosure include corn starch, fluorinated glucose, metabolites of the fluorinated glucose or croScarmelose sodium, crospovidone (polyplasdone XL-10), combinations of the fluorinated glucose and metabolites of sodium starch glycolate (EXPLOTAB or PRIMOJEL) or any the fluorinated glucose; and combination of the foregoing. 0121 iv) detecting the fluorinated glucose, metabolites of 0.130. The solid composition should be designed to dis the fluorinated glucose or combinations of the fluorinated solve rapidly in the oral cavity, be chewed or release all of the glucose and metabolites of the fluorinated glucose in the fluorinated glucose into the stomach or gastrointestinal tract Subject using the MRSI and obtaining an image of the desired within 5 to 30 minutes upon ingestion. In an embodiment of region of the subject embodiments of the present disclosure the present disclosure, the solid composition is a 25 to 2000 US 2014/0285.191 A1 Sep. 25, 2014 mg oral tablet, preferably a 50 to 1500mg oral tablet and most different molecules including pharmaceuticals (human and preferably a 100 to 1000 mg oral tablet. Veterinary) cosmeceuticals and neutraceuticals, agricultural 0131 The liquid compositions may be in the form of a chemicals, proteins, carbohydrates, etc. In a preferred Solution or Suspension that is capable of being orally admin embodiment, CF, CHF CHF, etc., groups could be substi istered, i.e., drunk, by the patient. These liquid compositions tuted for CH and all these groups attached to C. S, N, etc. comprise the fluorinated glucose and a liquid carrier Such as and/or added to a wide variety of molecules So as to make the water, alcohol or a mixture of water and alcohol. The liquid F' magnetization of the molecules easier to detect/distin oral compositions may further comprise conventional phar guish. maceutical excipients such as preservatives, antimicrobial 0.136 Further, it is believed that existing fluorinated mol agents, buffers, pH adjusting agents, flavoring agents, dyes or ecules such as FASLODEX (fulvestrant), NEXAVAR (sor combinations thereof. A more detailed description of the afenib) STIVARGA (regorafenib), a non-radioactive form of acceptable pharmaceutical excipients that may be employed AMYVID (fluorbetapir), BANZEL (rufinamide), ZELBO in the liquid compositions of the present disclosure can be RAF (vemurafenib) and 5-fluorouracil may be useful for found in Rowe et al., Handbook of Pharmaceutically Accept imaging employing the SR and SSR technology described able Excipients (4" ed. 2003) or the United States Pharma herein. copeia 29, both of which are incorporated herein by refer 0.137 The SSR employed in the method for detecting and/ CCC. or imaging fluorinated glucose and/or metabolites of fluori 0132) The liquid compositions may also be compositions nated glucose in vivo in a subject that employs the SR and that can be administered parentally, i.e., intravenously or SSR technology described herein should comprise about 0.1 intramuscularly. The liquid compositions for parenteral to about 1% by volume, preferably 0.5% by volume of FDG, administration will comprise the fluorinated glucose and a FDG-6-P or a combination thereof. In a preferred embodi liquid carrier, preferably water for injection. The parenteral ment, the SSR will comprise at least 10 grams of FDG alone, liquid compositions may further comprise conventional phar at least 10 grams of FDG-6-P alone or a combination of at maceutical excipients such as preservatives, antimicrobial least 10 grams of FDG and at least 10 grams of FDG-6-P. agents, buffers, pH adjusting agents, tonicity agents, antioxi 0.138. As concluded by Ruiz-Cabello et al. in Fluorine dants or combinations thereof. A more detailed description of (F) MRS and MRI In Biomedicine, NMR in Biomedicine, the acceptable pharmaceutical excipients and methods for (2011): 24, 114-129 (hereinafter, “Ruiz-Cabello”, which is preparing them can be found in Remington, The Science and incorporated by reference herein in its entirety), low SNR Practice of Pharmacy 21st ed. 2005, pp. 802-847 which are remains a challenge in imaging molecules including F incorporated herein by reference. In an embodiment of the because of the intrinsically low 'F concentrations in vivo. present disclosure, the liquid composition is an intravenous However, Applicants have appreciated that virtually all if not Solution comprising 5% fluorinated glucose (50 mg/ml) in all of the techniques and molecules used and results obtained normal saline, sodium citrate and citric acid to adjust the pH in Ruiz-Cabello can be improved upon drastically when to about 6.2. imaging 'F using Superradiant techniques as disclosed 0133. It is estimated based upon the known pharmacoki herein, thus solving many long felt, but unresolved, problems netics for glucose and FDG that the amount of fluorinated in the field of MR imaging. As observed by Ruiz-Cabello, for glucose to be administered to a sample to allow imaging with 'F MRI to produce an image quality similar to that of H an MRSI device in accordance with the present disclosure MRI, whose signal derives from nearly two-thirds of all will be in the range of about 10 mg/kg to about 200 mg/kg, nuclei present in the body, the agent benefits from a very high preferably about 25 mg/kg to about 100 mg/kg, more prefer density of 19F nuclei on the molecule in addition to a high ably about 35 mg/kg to about 65 mg/kg and most preferably tissue concentration. Perfluorination can provide a compa about 50 mg/kg. A person of ordinary skill can easily calcu rable density of 'F nuclei when one, more than one, or all H late the amount of FDG to be administered to the sample and nuclei on a hydrocarbon chain are replaced. Perfluorocarbons the amount of the solid or liquid composition described above (PFCs) are molecules of similar structure to common organic that will provide the desired dosing range. compounds (e.g. alkanes), except that all of the hydrogen 0134. The fluorinated glucose composition should be atoms are replaced by fluorine. These agents are well Suited administered to the patient under fasting conditions. Prefer for medical applications. ably, the patient should refrain from eating or drinking any I0139 Liquid PFCs have a low water solubility, which thing but water or black coffee for at least four (4) hours, leads to slow diffusion and a long tenancy at the target site of preferably six (6) hours, prior to administration of the fluori the compound in its natural form. Although PFCs are lipo nated glucose composition. Most preferably the patient phobic, because the degree of lipophobicity is commonly less should have a plasma glucose level of less than 150 mg/dL, than the hydrophobicity, PFCs tend to partition into the lipid preferably less than 125 mg/dL and most preferably 100 component of cellular membranes and, in Some cases, affect mg/dL or less at the time of administration. Once the fluori the cellular response to certain stimulants and stressors. The nated glucose composition is administered to the patient, the depth of penetration and the penetration rate can be modu imaging should begin within 10 to 90 minutes, preferably lated as a function of the particle size and the lipid solubility within 20 to 60 minutes if the composition is administered of emulsions prepared with different PFCs. PFCs are also intravenously and within 20 to 150 minutes, preferably within characterized by a very low Surface tension, which make them 30 to 120 minutes following oral administration. attractive for certain applications (e.g. intra-alveolar). An 0135 Additional molecules other than fluorinated glucose effective fluidity (viscosity) and a positive coefficient of and choline can be specifically prepared so as to enhance their spreading allow these molecules to spread evenly over a Sur capacity for detection and/or distinguishability using the SR face. and SSR technologies described herein. As a non-exclusive 0140. A first group of applications, based on the direct example, F can be added singly or in multiples to many detection of fluorinated molecules using SR in accordance US 2014/0285.191 A1 Sep. 25, 2014

with the disclosure, cell tracking using PFC emulsions and in body. For this reason, PFCs are commonly combined in com Vivo monitoring of fluorinated drugs and their metabolites. mercial products to optimize the stability and clearance pro An example is the use of F superradiant MRS techniques for file. For example, perfluorodecalin (PFDC) is rapidly cleared the detection of 5-fluorouracil (5-FU), a chemotherapeutic from the body, but forms emulsions that have poor stability. agent. As a result of the low tissue concentration of 5-FU (in However, perfluorotripropylamine (PFTPA) forms stable the mmol/g wet weight range) and fluorine-containing phar emulsions that have a long retention time. By combining maceuticals used at clinical doses, the sensitivity of F super these two agents, emulsions such as Fluosol Rachieve both a radiant MRS and MRI depends primarily on the number of clinically acceptable stability and clearance profile. Never fluorine atoms present in the compound and the dose, in theless, Fluosol(R) emulsions remain stable for only about six addition to the conventional factors that determine SNR, such hours after PFDC and PFTPA are mixed. Consequently, as the magnetic field strength, detector design, and the like. PFDC and PFTPA emulsions are stored frozen in separate 0141. A second group of applications includes examples Solutions, and the Solutions are thawed and mixed immedi in which the fluorine molecules respond to a specific param ately prior to use. For practicality and other reasons, this eter, such as the presence of ligands. Fluorinated compounds version of the product was replaced in 1994 by a new PFDC/ are capable of detecting changes in oxygen, H (pH), Na", PFTPA preparation, Oxygent(R), that has proven to be much Ca" and Mg" concentrations in biological tissues, and may more stable, and does not require frozen storage. therefore provide proxy measurements of these. Paramag (0145 Perfluoropolyethers (PFPEs) (e.g. containing 12, 15 netic relaxation effects can be imparted by oxygen on 'F or 18 crown ethers) are excellent F MRI contrast agents as nuclei, which cause changes in the spin-lattice relaxation they provide a single sharp resonance, eliminating any chemi rates (1/T), and can alter the chemical shift of one or more of cal shift artifact, maximizing the SNR and allowing an unam the fluorine moieties. Changes associated with temperature biguous identification of the PFC. Nanoparticle preparations and blood flow in the microenvironment may also affect the of Some of these agents are thermodynamically stable (they 'F signals. In addition to the limits imposed by the low in do not coalesce) and can be prepared using several different vivo F concentration of the agent being used, the utility of types of emulsifying agent that form a film around the dis the 'Fagent as aproxy largely depends on the magnitude and persed globules of PFC. Typical emulsifying agents are Sur sensitivity of the changes that are elicited. face-active agents, adsorbing at oil-water interfaces to form 0142. Also included in this second group is the use of monomolecular films that reduce the interfacial surface ten fluorinated emulsions in "H MRI applications. One type of Sion. A large variety of agents have been used to improve the PFC., PFOB, has been shown to be an effective negative stability (lecithin is one of the most commonly used) and to contrast agent for delineating the bowel and improving bowel increase the effective encapsulation of PFCs. In practice, wall visualization. The bowellumina appear homogeneously combinations of emulsifiers are commonly used, rather thana black on T1- and T2-weighted MR images because of the single agent (e.g., Safflower oil and lecithin, cholesterol and insolubility of PFOB in water and intestinal secretions. lecithin, etc.). This enables the modification and optimization of the balance between the hydrophilic and lipophilic parts of Preparation and Chemical Stability of PFCs the emulsifier or mixture of emulsifiers. 0143. The PFCs used in biomedical applications are 0146 The addition of other agents to a PFC emulsion can chemically inert. They are derived synthetically, consist pri improve its performance from an MRI/MRS standpoint, but marily of carbon and fluorine atoms, and are typically clear, can also affect the stability of the preparation. For example, colorless liquids that are insoluble in water. They should adding fluorescent lipids, cationic transfection reagents (lipo therefore be emulsified for clinically relevant applications fectamine) or targeted ligands to PFCs provides a means to involving intravenous injection, intraperitoneal injection, tis detect the agents by fluorescence microscopy, to enhance Sue intraparenchymal injection or administration in oxygen cellular labeling or to perform molecular imaging, respec permeable biodegradable and biocompatible capsules. The tively. A number of drugs, including antibacterial agents, process is analogous to the routine preparation of lipid emul vasoactive bronchodilators, mucolytic agents, glucocorti sions for parenteral nutrition. Despite the intrinsically low coids, antineoplastic agents and DNA, have also been incor solubility, diffusivity, density and interfacial surface tension porated into PFC emulsions without reducing their stability. of PFCs, it is possible to generatestable nanoparticles of these These drugs offer significant value as the PFC phase can compounds using a high-pressure micro-emulsifier. The lat contain a high payload of hydrophobic drugs. ter deagglomerates and disperses Submicrometer PFC par ticles uniformly in the fluid. This results in a smaller particle 19F Superradiant MRS of Drug Metabolism size compared with unpressurized emulsification, which, in 0.147. In one embodiment, SR enhances detection of mol turn, permits higher PFC concentrations 40% and higher— ecules by increasing the available signal averaging rate. This to be achieved. The nanoparticles obtained with this proce permits molecules to be detected in concentrations lower than dure typically have a very Small size. Nominal particle sizes those that can be utilized in otherwise standard NMR/MRI/ can range, for example, from about 100 nm-300 nm for vari MRS experiments. The level of sensitivity increase, for a ous formulations, in any increment of 5 nm (e.g., about 150 given magnetic field, RF coil depends on the ratio of T1?t 250 nm, about 100-200 nm, about 200-300 nm, about 100 where to as defined above the surperradiant time, the time 150 nm, about 150-200 nm, about 200-250 nm, about 250 required under SR conditions to return all magnetization to 300 nm, and the like). However, the stability of commercially equilibrium. available PFC preparations varies greatly, and there is a direct 0148 Under standard clinical conditions T1 of many flu relationship between PFC stability and the clearance time orinated molecules tend to be in the 1 second range in vivo. from the body. Using an FECTS as Small as 1 msec have been produced. 0144. From a design standpoint, most clinical applications Thus the level of SNR enhancement for a fluorinated mol require stable preparations that are rapidly cleared from the ecule with a t1 of 1 second is SQRT (1000) or -32. Thus if 10 US 2014/0285.191 A1 Sep. 25, 2014

mM of a given molecule may be detected in a standard MRI/ complex systems, such as the maintenance of intracellular pH MRS experiment, using SR one could detect -0.3 mM using in different cell lines, and intracellular free calcium and mag SR enhanced MR technique described herein. nesium levels via fluorinated chelates. A good exogenous Ph 0149 Applicant believes that F superradiant MRS can indicator should have favorable pharmacokinetics, i.e. anion provide a highly specific tool for the investigation of drugs izable group with a pK value in the physiological range, good and their metabolic byproducts that contain fluorine atoms, sensitivity and specificity, low toxicity, efficient cell penetra which is also potentially Suitable for quantification, particu tion, fast exchange between acid and base forms, but slow larly when combined with the teachings of Superradiance exchange across cell membranes, and a large chemical shift herein. The most commonly used drugs in F conventional range (10, 40-43). The intracellular uptake and concentration NMR are listed in Table 1. Their relative 'F SNRs, when should be high enough to provide adequate SNR from just the present at a tissue concentration of 1 mmol/g wet weight, are intracellular space. It is believed that the intracellular concen also listed. tration of different cations can also be obtained from the TABLE 1. List of PF drugs and therapeutic agents Commercial name Chemical Relative SNR Agent or acronym formula Modality Application Physical state (reference) 5,5'-Difluoro-1,2-bis FBAPTA C22H22F2N2Oo MRS Calcium chelator Solution 2.1 x 10 (46) (o-amino-phenoxy) ethane-N,N,N',N'- tetraacetic acid 5-Fluorouracil Efudex (R) CHFN2O2 MRI, MRS Antineoplastic Saline solution 1.0 x 10 (8, 12, 27, 30, 34, 36-38, 42, 105) Flurbiprofen Adfeed, Ansaid C15HFO- MRS Anti-inflammatory Gel, oral 1.0 x 10 (106) tablets Fluorodeoxyglucose FDG CHFOs MRS Inhibitor Solution 1.0 x 10° (17) Deoxy-fluouridine Capecitabine C15H2FNO MRS Prodrugs, Oral tablets, 1.0 x 10 (pro-drug) (Xeloda (R) antineoplastic injectable (105, 107) Fluoxetine Prozac (R) C17H8FNO, MRS Antidepressant Capsule, liquid 3.1 x 10 (108) hydrochloride HC solutions Fluvoxamine Dumitrox C15H2F3N2O2 MRS Antidepressant Oral tablet 3.1 x 10 (109, 110) Flurazepam Dalmane, Felison C2H2CIFNO MRS Anti-anxiolytic Capsule 1.0 x 10 (111) Fluoexetine Prozac (R), Sarafem (R) C7HFNO MRS Antidepressant Capsule, syrup 3.1 x 10 (112, 113) Floxuridine Fudr (R) CoHFNOs MRS Antineoplastic Injectable 1.0 x 10 (107) Gefinitib Iressa (R) C22H2CIFNO MRS Antineoplastic Oral tablet 1.0 x 10 (114) a19E signal-to-noise ratio (SNR) of the fluorinated agentata concentration of 1 umol/g wettissue weight relative to the H signal detected from an equivalent tissue volume with a detector coil of the same geometry, The calculation assumes a tissue water content of 76.5% (+0.37SD), which is an average of the water contents of brain, skeletal muscle and liver tissues (115), and sample-dominant noise resulting in a linear-dependent SNR with field strength, And references therein. 0150. The study of such drugs by F MRI/MRS tends to change in the 'F superradiant NMR spectrum of an indicator focus on their chemical structure, anabolism, catabolism, dis cation to which it is bound. Ca" plays an important role as a tribution and pharmacokinetics in Vivo and in excised tissues. second messenger in living cells. F-based methods have As an example, 'FMRS has been used widely in pharmaco been proposed for the determination of cytosolic calcium in kinetic studies of the anticancer drug 5-FU. As an anticancer cells and tissues. It is also possible to detection this cellular agent, 5-FU has been applied in concomitant radiotherapy cation by way of the use of 1.2-bis(o-aminophenoxy)ethane and chemotherapy of different neoplastic diseases, particu N.N.N',N'-tetraacetic acid (BAPTA). Here, the 'F-NMR larly for neoplasms of the colorectal system, the head and Ca" indicator is derived from its symmetrically 5,5-substi neck, the trunk and some breast cancers. As a result of the tuted difluoro-derivative (FBAPTA), which exhibits a chemi intrinsic toxicity of 5-FU, different pro-drugs (a drug in its cal shift response on binding calcium. One issue for intracel nonactive form) of the molecule have been designed to pass lular interrogation of any reporter molecule is the loading of intact through the gastrointestinal tract, ultimately localizing the reporter molecule into cells. As tetracarboxylate does not and selectively converting to 5-FU in the malignant tissue, penetrate the cell, a lipophilic agent, such as acetoxymethyl, based on the higher activity of thymidine phosphorylase. is used. Other 'F-bearing ligands can be used ions such as Capecitabine is one such protodrug designed in an oral for Na+, Mg2+, Zn2+. Pb2+, etc. Examples of these ligands are mulation to provide higher accumulation of 5-FU in the presented in Yu J X et al., 19F: a Versatile Reporter for tumor, whilst reducing the exposure of healthy tissues to Non-Invasive Physiology and Pharmacology. Using Mag 5-FU. All of these techniques can be practiced using Super netic Resonance, Curr. Med. Chem. 2005: 12: 819-848, radiant techniques as set forth herein. Such a practice is likely which is incorporated by reference herein in its entirety. to lead to significantly improved results. Applicant Submits that all of these techniques can be prac 'F Superradiant MRS of Extracellular pH and Cations in ticed using Superradiant techniques as set forth herein. Cells and Tissues Molecular and Cellular 'F Superradiant MRSI 0151. Applicant further believes that F superradiant 0152 MRI is able to visualize cells in vivo in real time. MRS can also be useful for observing biological processes in When cells are imaged in living animals, it can provide new US 2014/0285.191 A1 Sep. 25, 2014 insights into the biology of cell trafficking and migration. An 'F superradiant MRI or MRS, when present in sufficient example is the homing of white blood and hematopoietic cells concentration. For example, the distribution of 2-fluoro in cancer and immunological diseases. Because MRI meth 18F-2-deoxy-glucose, a widely used positron emission ods are noninvasive, they can be applied repeatedly to moni tomography probe for the measurement of abnormal glucose tor targeted cells and cellular processes. For cells to be visu consumption in tumors and ischemia, has been monitored alized by MRI, they generally must be labeled to enable their with "FMRS after replacing the unstable Fatom with 'F. discrimination from Surrounding tissue. Incorporation of PFCs into Cellular Therapeutic Biomaterials I0153. It is also possible to produce passively "F fluorine (O157. The incorporation of PFCs into biomaterials is labeled macrophages. When imaged in accordance with attractive for a number of reasons. By exploiting the various Superradiant techniques, these can be expected to appear as features of PFCs, fluorinated biomaterials can be used to hotspots in the central nervous system, for example in create Smart scaffolds that are capable of producing an oxy experimental allergic encephalomyelitis. This is an animal gen-rich environment whilst permitting the noninvasive model for multiple sclerosis which is characterized by infil assessment of biological parameters, such as O tension, pH tration of the macrophages into the inflamed brain. After and metabolite concentrations, with 'F MRI. Applicant induction of the disease, cells can be observed after intrave believes that fluorinated biomaterials, in conjunction with 'F nous injection of a PFCE emulsion, such as at a dose of about Superradiant MRI, can provide important information on the 3 g/kg. PFCs can also be used in accordance with the SR delivery and long-term survival of cellular therapeutics. For teachings herein to image macrophage infiltration in the inf these reasons, fluorinated biomaterials show promise for both arcted myocardium. Using different PFC preparations with the assessment and enhancement of the long-term viability of different 'F spectral frequencies (as 'signatures), Applicant cellular therapeutics after transplantation, particularly when believes it to be possible that multiple cell populations, employing SR techniques. labeled differently, can be detected simultaneously, when 0158 To date, the use of fluorinated biomaterials gener using SR techniques as described herein. PFCE can be used in ally in the art has been limited to PFC-containing microcap different mixtures of lipids to formulate emulsified cationic Sules. The use of microcapsules to provide the immuno-iso and anionic nanoparticles, for example, including fluorescent lation of cellular therapeutics has clinical potential for a wide rhodamine to tag different cells. range of diseases that require enzyme or endocrine replace 0154) A different research area within molecular and cel ment therapy. Applicant believes that its is possible to incor lular MRI is the use of transfected enzymes (reporter genes) porate PFPE emulsions in alginate/poly-L-lysine (PLL) that can convert a pro- (precursor) drug. In this technique, a microcapsules to enable the assessment of the biodistribution gene with specific enzymatic activity is first introduced into and integrity of microcapsules with SR MRI. As PFCs are tumor or other cells of interest. Then, a pro-drug is adminis rapidly cleared from the body when they are no longer encap tered and, on internalization of the pro-drug into cells, it is sulated, it is believed that SR MRI can provide a means of converted by the transgene into an active drug. This method assessing capsule rupture and loss of immunoprotection. ensures that the drug will be active only in the target cells and will not affect other tissues. A similar example involves 5-FU, Improved MRS wherein yeast cytosine deaminase is introduced into an HT29 colon carcinoma cell line to convert the precursor 5-fluoro 0159. Magnetic Resonance Spectroscopy is concerned cytosine (5-FC) into 5-FU, and elicit a chemotherapeutic with the identification of target molecules, usually in Vivo, response. The formation of 5-FU, measured in xenografted that are associated with specific disease states or other tumors using 'F MRS, when employing superradiant tech pathologies. This process is often complicated by the fact that niques as described herein, can provide an indication of the the in vivo environment has many molecules in it that crowd efficacy of drug delivery. By this technique, Applicants the MR spectrum. believe that 'F superradiant MRS can provide a means of 0160 Applicant has discovered that by adjusting the monitoring and optimizing the administration of Such pro parameters of the feedback field generated in SR conditions drugs to patients for chemotherapy. individual resonances can be highlighted or Suppressed as (O155 With regard to the use of 'F probes as 'smart trac desired. In a preferred embodiment, the phase, gain or both of ers' or molecular beacons, Applicant believes that 'F the FEC are adjusted so as to influence the frequency spec superradiant MRS can be employed to probe the enzymatic trum that is obtained as a result of carrying out a Fourier activity of a prototype reporter enzyme, b-galactosidase. This Transform (FT) of the SR time domain pulse. Specifically, the enzyme has been shown to liberate aglycone from the Sub size and width of a target resonance can be increased or strate 4-fluoro-2-nitrophenyl-b-D-galactopyranoside, result decreased as desired, highlighting it or Suppressing it relative ing in a pH-dependent 19F chemical shift of 5-10 ppm that to other resonances. Similarly, the frequency position of a can be used to measure intracellular pH. Other enzymes can target resonance may be shifted as a result of adjusting the one be probed as well. For example, certain proteases (caspase-3), or both of the gain and phase of the FEC. which are overexpressed in tumors, are able to cleave para (0161 Unlike traditional FT MRS, the FT of an SR peak magnetic chelates from fluorinated molecules, thereby modu cannot be a priori associated with specific positions in the lating 'F relaxation times and signal intensity. Finally, tem frequency spectrum and hence, without additional informa perature-sensitiveliposomes containing 'F tracers have been tion, identified with a particular molecule. In this case the developed as beacons for image-guided drug delivery. Appli additional information is the known composition and quan cant believes that each of these examples can be practiced tity of the molecules in the SSR, which the operator may using Superradiant imaging techniques as provided herein select in advance. Selection of the molecules in the SSR, as with superior results. well as control over the FEC, allows the operator to know 0156. In addition to enzymes, fluorinated metabolic sub which molecules in the sample or subject are in SR condi strates are also potential targets of study that are accessible to tions, and which are not. Thus observation of the SR pulse, as US 2014/0285.191 A1 Sep. 25, 2014

well as the FT of that pulse, can be used to carry out identi trackball, lightpen, or the like. A computer control and recon fication and/or quantification of a target molecule or mol struction module 58 is also provided that includes hardware ecules. and Software for enabling the operator to select among a (0162 FIG.5 shows the result of a FourierTransform of the plurality of preprogrammed magnetic resonance sequences SR pulse resulting from inversion of a simulated sample that are stored in a sequence control memory, if rf pulses are containing equal amounts of two resonances labelled 1 and 2. to be used as a part of the imaging study. A sequence control The simulation assumes that inside the SSR is a large amount ler 60 controls gradient amplifiers 62 connected with the of resonance 1 whose identity and quantity are known to the gradient coil assembly 30 for causing the generation of the operator. The phase angle of the “FEC was set to -120 GX, Gy, and GZ gradient magnetic fields at appropriate times degrees and the gain to 4 (arbitrary units in this simulation). during the selected gradient sequence and a digital transmitter The result is that the ratio of the peak of resonance 1 to 64 which causes a selected one of the whole body and insert resonance 2, which would be 1 in a traditional MR protocol, able radio frequency coils to generate B radio frequency field is 31 times greater after the resultant SR pulse is Fourier pulses at times appropriate to the selected sequence, if rf Transformed. This makes it much easier to identify the pres pulses are to be used in the study. ence and quantity of Resonance 1. 0168 MR signals received by the coil 40 are demodulated 0163. In some embodiments, spatially encoded electro by a digital receiver 66 and stored in a data memory 68. The magnetic feedback can be induced at least in part by Substan data from the data memory are reconstructed by a reconstruc tially eliminating the presence of a gradient magnetic field in tion or array processor 70 into a Volumetric image represen the at least one region of interest while maintaining it in tation that is stored in an image memory 72. If a phased array others. In this context “spatially encoded electromagnetic is used as the receiving coil assembly, the image can be feedback’ means arranging for feedback to occur in one or reconstructed from the coil signals. A video processor 74 more regions of interest of a sample or Subject, while Sup under operator control converts selected portions of the volu pressing it in others. The region of interest can include, for metric image representation into slice images, projection example, at least one voxel, and the at least one gradient coil images, perspective views, or the like as is conventional in the can be adapted and configured to apply a magnetic field art for display on the video monitor. gradient in at least one of three mutually orthogonal direc tions. This permits spectroscopic identification of target mol Example ecules in selected regions of space. (0164. Exemplary MRI Scanner Systemization MKTTM Controller 0165 An exemplary magnetic resonance system is (0169 FIG. 7 illustrates inventive aspects of a MKTTM depicted in FIG. 6, and includes a plurality of primary mag controller 601 for controlling a system such as that illustrated netic coils 10 that generate a uniform, temporally constant in FIG. 6 implementing some of the embodiments disclosed magnetic field Bo along a longitudinal or Z-axis of a central herein. In this embodiment, the MKTTM controller 601 may bore 12 of the device. In a preferred superconducting embodi serve to aggregate, process, store, search, serve, identify, ment, the primary magnet coils are supported by a former 14 instruct, generate, match, and/or facilitate interactions with a and received in a toroidal helium vessel or can 16. The vessel computer through various technologies, and/or other related is filled with helium to maintain the primary magnet coils at data. Superconducting temperatures. The can is Surrounded by a (0170. With respect to the controller 601, typically, a user series of cold shields 18 which are supported in a vacuum or users, e.g., 633a, which may be people or groups of users Dewar 20. Of course, annular resistive magnets, C-magnets, and/or other systems, may engage information technology and the like are also contemplated. systems (e.g., computers) to facilitate operation of the system 0166 A whole body gradient coil assembly 30 includes X, and information processing. In turn, computers employ pro y, and Z-coils mounted along the bore 12 for generating gra cessors to process information; such processors 603 may be dient magnetic fields, Gx, Gy, and GZ. Preferably, the gradi referred to as central processing units (CPU). One form of ent coil assembly is a self-shielded gradient coil that includes processor is referred to as a microprocessor. CPUs use com primary X, y, and Z-coil assemblies 32 potted in a dielectric municative circuits to pass binary encoded signals acting as former and secondary X, y, and Z-coil assemblies 34 that are instructions to enable various operations. These instructions Supported on a bore defining cylinder of the vacuum Dewar may be operational and/or data instructions containing and/or 20. A whole body radio frequency coil 36 can be mounted referencing other instructions and data in various processor inside the gradient coil assembly 30. A whole body radio accessible and operable areas of memory 629 (e.g., registers, frequency shield 38, e.g., copper mesh, can be mounted cache memory, random access memory, etc.). Such commu between the whole body RF coil 36 and the gradient coil nicative instructions may be stored and/or transmitted in assembly 30. If desired, an insertable radio frequency coil 40 batches (e.g., batches of instructions) as programs and/or data can be removably mounted in the bore in an examination components to facilitate desired operations. These stored region defined around an isocenter of the magnet 10. In the instruction codes, e.g., programs, may engage the CPU circuit embodiment of FIG. 2, the insertable radio frequency coil is components and other motherboard and/or system compo ahead and neck coil for imaging one or both of patient's head nents to perform desired operations. One type of program is a and neck, but other extremity coils can be provided. Such as computer operating system, which, may be executed by CPU back coils for imaging the spine, knee coils, shoulder coils, on a computer; the operating system enables and facilitates breast coils, wrist coils and the like. users to access and operate computer information technology 0167. With continuing reference to FIG. 6, an operator and resources. Some resources that may be employed in interface and control station is provided that includes a information technology systems include: input and output human-readable display, such as a video monitor 52, and mechanisms through which data may pass into and out of a operator input devices such as a keyboard 54, a mouse 56, a computer, memory storage into which data may be saved; and US 2014/0285.191 A1 Sep. 25, 2014 processors by which information may be processed. These otherwise transportive circuit pathways through which information technology systems may be used to collect data instructions (e.g., binary encoded signals) may travel to effect for later retrieval, analysis, and manipulation, which may be communications, operations, storage, etc. Optionally, the facilitated through a database program. These information computer systemization may be connected to an internal technology Systems provide interfaces that allow users to power Source 686; e.g., optionally the power source may be access and operate various system components. internal. Optionally, a cryptographic processor 626 and/or (0171 In one embodiment, the MKTTM controller 601 may transceivers (e.g., ICs) 674 may be connected to the system be connected to and/or communicate with entities such as, but bus. In another embodiment, the cryptographic processor not limited to: one or more users from user input devices 611; and/or transceivers may be connected as eitherinternal and/or peripheral devices 612, components of the magnetic reso external peripheral devices 612 via the interface bus I/O. In nance system; an optional cryptographic processor device turn, the transceivers may be connected to antenna(s) 675, 628; and/or a communications network 613. For example, the thereby effectuating wireless transmission and reception of MKTTM controller 601 may be connected to and/or commu various communication and/or sensor protocols; for example nicate with users, e.g., 633a, operating client device(s), e.g., the antenna(s) may connect to: a Texas Instruments WiLink 633b, including, but not limited to, personal computer(s), WL1283 transceiver chip (e.g., providing 802.11n, Bluetooth server(s) and/or various mobile device(s) including, but not 3.0, FM, global positioning system (GPS) (thereby allowing limited to, cellular telephone(s), Smartphone(s) (e.g., MKTTM controller to determine its location)); Broadcom iPhone(R), Blackberry(R), Android OS-based phones etc.), tab BCM4329FKUBG transceiver chip (e.g., providing 802.11n, let computer(s) (e.g., Apple iPadTM, HP SlateTM, Motorola Bluetooth 2.1+EDR, FM, etc.); a Broadcom BCM4750IUB8 XoomTM, etc.), eBook reader(s) (e.g., Amazon KindleTM, receiver chip (e.g., GPS); an Infineon Technologies X-Gold Barnes and Noble's NookTM eReader, etc.), laptop computer 618-PMB9800 (e.g., providing 2G/3G HSDPA/HSUPA (s), notebook(s), netbook(s), gaming console(s) (e.g., XBOX communications); and/or the like. The system clock typically LiveTM, Nintendo(R DS, Sony PlayStation(R) Portable, etc.), has a crystal oscillator and generates a base signal through the portable scanner(s) and/or the like. computer systemization's circuit pathways. The clock is typi 0172 Networks are commonly thought to comprise the cally coupled to the system bus and various clock multipliers interconnection and interoperation of clients, servers, and that will increase or decrease the base operating frequency for intermediary nodes in a graph topology. It should be noted other components interconnected in the computer systemiza that the term “server” as used throughout this application tion. The clock and various components in a computer sys refers generally to a computer, other device, program, or temization drive signals embodying information throughout combination thereof that processes and responds to the the system. Such transmission and reception of instructions requests of remote users across a communications network. embodying information throughout a computer systemiza Servers serve their information to requesting “clients.” The tion may be commonly referred to as communications. These term "client’ as used herein refers generally to a computer, communicative instructions may further be transmitted, program, other device, user and/or combination thereofthat is received, and the cause of return and/or reply communica capable of processing and making requests and obtaining and tions beyond the instant computer systemization to: commu processing any responses from servers across a communica nications networks, input devices, other computer systemiza tions network. A computer, other device, program, or combi tions, peripheral devices, and/or the like. Of course, any of the nation thereof that facilitates, processes information and above components may be connected directly to one another, requests, and/or furthers the passage of information from a connected to the CPU, and/or organized in numerous varia Source user to a destination user is commonly referred to as a tions employed as exemplified by various computer systems. “node.” Networks are generally thought to facilitate the trans 0176 The CPU comprises at least one high-speed data fer of information from source points to destinations. A node processor adequate to execute program components for specifically tasked with furthering the passage of information executing user and/or system-generated requests. Often, the from a source to a destination is commonly called a “router.” processors themselves will incorporate various specialized There are many forms of networks such as Local Area Net processing units, such as, but not limited to: integrated system works (LANs), Pico networks, Wide Area Networks (WANs). (bus) controllers, memory management control units, floating Wireless Networks (WLANs), etc. For example, the Internet point units, and even specialized processing Sub-units like is generally accepted as being an interconnection of a multi graphics processing units, digital signal processing units, tude of networks whereby remote clients and servers may and/or the like. Additionally, processors may include internal access and interoperate with one another. fast access addressable memory, and be capable of mapping (0173 The MKTTM controller 601 may be based on com and addressing memory 629 beyond the processor itself; puter systems that may comprise, but are not limited to, internal memory may include, but is not limited to: fast reg components such as: a computer systemization 602 con isters, various levels of cache memory (e.g., level 1, 2, 3, etc.), nected to memory 629. RAM, etc. The processor may access this memory through 0.174 Computer Systemization the use of a memory address space that is accessible via 0.175. A computer systemization 602 may comprise a instruction address, which the processor can construct and clock 630, central processing unit (“CPU(s)' and/or “proces decode allowing it to access a circuit path to a specific sor(s)' (these terms are used interchangeable throughout the memory address space having a memory state. The CPU may disclosure unless noted to the contrary)) 603, a memory 629 be a microprocessor such as: AMD's Athlon, Duron and/or (e.g., a read only memory (ROM) 606, a random access Opteron; ARM’s application, embedded and secure proces memory (RAM) 605, etc.), and/or an interface bus 607, and sors; IBM and/or Motorola's DragonBall and PowerPC; most frequently, although not necessarily, are all intercon IBM's and Sony's Cell processor; Intel's Celeron, Core (2) nected and/or communicating through a system bus 604 on Duo, Itanium, Pentium, Xeon, and/or XScale; and/or the like one or more (mother)board(s) 602 having conductive and/or processor(s). The CPU interacts with memory through US 2014/0285.191 A1 Sep. 25, 2014 instruction passing through conductive and/or transportive like. Other types of AC or DC power sources may be used as conduits (e.g., (printed) electronic and/or optic circuits) to well. In the case of Solar cells, in one embodiment, the case execute stored instructions (i.e., program code) according to provides an aperture through which the Solar cell may capture conventional data processing techniques. Such instruction photonic energy. The power cell 686 is connected to at least passing facilitates communication within the MKTTM con one of the interconnected Subsequent components of the troller and beyond through various interfaces. Should pro MKTTM thereby providing an electric current to all subse cessing requirements dictate a greater amount speed and/or quent components. In one example, the power source 686 is capacity, distributed processors (e.g., Distributed MKTTM connected to the system bus component 604. In an alternative embodiments), mainframe, multi-core, parallel, and/or Super embodiment, an outside power source 686 is provided computer architectures may similarly be employed. Alterna through a connection across the I/O 608 interface. For tively, should deployment requirements dictate greater port example, a USB and/or IEEE 1394 connection carries both ability, smaller Personal Digital Assistants (PDAs) may be data and power across the connection and is therefore a Suit employed. able source of power. 0177 Depending on the particular implementation, fea 0181 Interface Adapters tures of the MKTTM implementations may be achieved by 0182 Interface bus(ses) 607 may accept, connect, and/or implementing a microcontroller such as CAST's R8051XC2 communicate to a number of interface adapters, convention microcontroller; Intel's MCS 51 (i.e., 8051 microcontroller); ally although not necessarily in the form of adapter cards, and/or the like. Also, to implement certain features of the such as but not limited to: input output interfaces (I/O) 608, MKTTM embodiments, some feature implementations may storage interfaces 609, network interfaces 610, and/or the rely on embedded components, such as: Application-Specific like. Optionally, cryptographic processor interfaces 627 simi Integrated Circuit (ASIC), Digital Signal Processing larly may be connected to the interface bus. The interface bus (“DSP), Field Programmable Gate Array (“FPGA'), and/or provides for the communications of interface adapters with the like embedded technology. For example, any of the one another as well as with other components of the computer MKTTM component collection (distributed or otherwise) and/ systemization. Interface adapters are adapted for a compat or features may be implemented via the microprocessor and/ ible interface bus. Interface adapters conventionally connect or via embedded components; e.g., via ASIC, coprocessor, to the interface bus via a slot architecture. Conventional slot DSP. FPGA, and/or the like. Alternately, some implementa architectures may be employed. Such as, but not limited to: tions of the MKTTM may be implemented with embedded Accelerated Graphics Port (AGP), Card Bus, (Extended) components that are configured and used to achieve a variety Industry Standard Architecture ((E)ISA), Micro Channel of features or signal processing. Architecture (MCA), NuBus, Peripheral Component Inter 0.178 Depending on the particular implementation, the connect (Extended) (PCI(X)). PCI Express, Personal Com embedded components may include Software solutions, hard puter Memory Card International Association (PCMCIA), ware solutions, and/or some combination of both hardware/ and/or the like. software solutions. For example, MKTTM features discussed 0183 Storage interfaces 609 may accept, communicate, herein may be achieved through implementing FPGAs. and/or connect to a number of storage devices such as, but not which area semiconductor devices containing programmable limited to: storage devices 614, removable disc devices, and/ logic components called “logic blocks, and programmable or the like. Storage interfaces may employ connection proto interconnects, such as the high performance FPGA Virtex cols such as, but not limited to: (Ultra) (Serial) Advanced series and/or the low cost Spartan series manufactured by Technology Attachment (Packet Interface) ((Ultra) (Serial) Xilinx. Logic blocks and interconnects can be programmed ATA(PI)), (Enhanced) Integrated Drive Electronics (E)IDE), by the customer or designer, after the FPGA is manufactured, Institute of Electrical and Electronics Engineers (IEEE) to implement any of the MKTTM features. A hierarchy of 1394, fiber channel, Small Computer Systems Interface programmable interconnects allow logic blocks to be inter (SCSI), Universal Serial Bus (USB), and/or the like. connected as needed by the MKTTM system designer/admin 0.184 Network interfaces 610 may accept, communicate, istrator, somewhat like a one-chip programmable breadboard. and/or connect to a communications network 613. Through a An FPGA's logic blocks can be programmed to perform the communications network 613, the MKTTM controller is function of basic logic gates such as AND, and XOR, or more accessible through remote clients 633b (e.g., computers with complex combinational functions such as decoders or simple web browsers) by users 633a. Network interfaces may mathematical functions. In most FPGAs, the logic blocks also employ connection protocols such as, but not limited to: include memory elements, which may be simple flip-flops or direct connect, Ethernet (thick, thin, twisted pair 10/100/1000 more complete blocks of memory. In some circumstances, the Base T, and/or the like), Token Ring, wireless connection MKTTM may be developed on regular FPGAs and then such as IEEE 802.11a-X, and/or the like. Should processing migrated into a fixed version that more resembles ASIC requirements dictate a greater amount speed and/or capacity, implementations. Alternate or coordinating implementations distributed network controllers (e.g., Distributed MKTTM), may migrate MKTTM controller features to a final ASIC architectures may similarly be employed to pool, load bal instead of or in addition to FPGAs. Depending on the imple ance, and/or otherwise increase the communicative band mentation all of the aforementioned embedded components width required by the MKTTM controller. A communications and microprocessors may be considered the “CPU” and/or network may be any one and/or the combination of the fol “processor for the MKTTM. lowing: a direct interconnection; the Internet, a Local Area 0179 Power Source Network (LAN); a Metropolitan Area Network (MAN); an 0180. The power source 686 may be of any standard form Operating Missions as Nodes on the Internet (OMNI); a for powering Small electronic circuit board devices such as secured custom connection; a Wide Area Network (WAN); a the following power cells: alkaline, lithium hydride, lithium wireless network (e.g., employing protocols such as, but not ion, lithium polymer, nickel cadmium, Solar cells, and/or the limited to a Wireless Application Protocol (WAP), I-mode, US 2014/0285.191 A1 Sep. 25, 2014 20 and/or the like); and/or the like. A network interface may be sources, visors, and/or the like. Peripheral devices often regarded as a specialized form of an input output interface. include types of input devices (e.g., cameras). Further, multiple network interfaces 610 may be used to 0188 Cryptographic units such as, but not limited to, engage with various communications network types 613. For microcontrollers, processors 626, interfaces 627, and/or example, multiple network interfaces may be employed to devices 628 may be attached, and/or communicate with the allow for the communication over broadcast, multicast, and/ MKTTM controller. AMC68HC16 microcontroller, manufac or unicast networks. tured by Motorola Inc., may be used for and/or within cryp 0185. Input Output interfaces (I/O) 608 may accept, com tographic units. The MC68HC16 microcontroller utilizes a municate, and/or connect to user input devices 611, periph 16-bit multiply-and-accumulate instruction in the 16 MHz eral devices 612, cryptographic processor devices 628, and/or configuration and requires less than one second to perform a the like. I/O may employ connection protocols such as, but 512-bit RSA private key operation. Cryptographic units sup not limited to: audio: analog, digital, monaural, RCA, Stereo, port the authentication of communications from interacting and/or the like; data: Apple Desktop Bus (ADB), IEEE agents, as well as allowing for anonymous transactions. Cryp 1394a-b, serial, universal serial bus (USB): infrared; joystick; tographic units may also be configured as part of CPU. keyboard; midi; optical; PC AT; PS/2; parallel; radio: video Equivalent microcontrollers and/or processors may also be interface: Apple Desktop Connector (ADC), BNC, coaxial, used. Other commercially available specialized crypto component, composite, digital, Digital Visual Interface graphic processors include: the Broadcom's CryptoNetX and (DVI), high-definition multimedia interface (HDMI), RCA, other Security Processors; nGipher's nShield, SafeNets RF antennae, S-Video, VGA, and/or the like; wireless trans Luna PCI (e.g., 7100) series: Semaphore Communications ceivers: 802.11a/b/g/n/x: Bluetooth; cellular (e.g., code divi 40 MHz Roadrunner 184: Sun's Cryptographic Accelerators sion multiple access (CDMA), high speed packet access (e.g., Accelerator 6000 PCIe Board, Accelerator 500 Daugh (HSPA(+)), high-speed downlink packet access (HSDPA), tercard); Via Nano Processor (e.g., L2100, L2200, U2400) global system for mobile communications (GSM), long term line, which is capable of performing 500+ MB/s of crypto evolution (LTE), WiMax, etc.); and/or the like. One typical graphic instructions: VLSI Technology's 33 MHz 6868; and/ output device may include a video display, which typically or the like. comprises a Cathode Ray Tube (CRT) or Liquid Crystal Dis (0189 Memory play (LCD) based monitor with an interface (e.g., DVI cir 0.190 Generally, any mechanization and/or embodiment cuitry and cable) that accepts signals from a video interface, allowing a processor to affect the storage and/or retrieval of may be used. The video interface composites information information is regarded as memory 629 (or 68, 72, etc.). generated by a computer systemization and generates video However, memory is a fungible technology and resource, signals based on the composited information in a video thus, any number of memory embodiments may be employed memory frame. Another output device is a television set, in lieu of or in concert with one another. It is to be understood which accepts signals from a video interface. Typically, the that the MKTTM controller and/or a computer systemization video interface provides the composited video information may employ various forms of memory 629. For example, a through a video connection interface that accepts a video computer systemization may be configured wherein the func display interface (e.g., an RCA composite video connector tionality of on-chip CPU memory (e.g., registers), RAM, accepting an RCA composite video cable; a DVI connector ROM, and any other storage devices are provided by a paper accepting a DVI display cable, etc.). punch tape or paperpunch card mechanism; of course such an 0186. User input devices 611 often are a type of peripheral embodiment would result in an extremely slow rate of opera device 612 (see below) and may include: card readers, tion. In a typical configuration, memory 629 will include dongles, finger print readers, gloves, graphics tablets, joy ROM 606, RAM 605, and a storage device 614. A storage Sticks, keyboards, microphones, mouse (mice), remote con device 614 may be any conventional computer system stor trols, retina readers, touch screens (e.g., capacitive, resistive, age. Storage devices may include a drum; a (fixed and/or etc.), trackballs, trackpads, sensors (e.g., accelerometers, removable) magnetic disk drive; a magneto-optical drive; an ambient light, GPS, gyroscopes, proximity, etc.), styluses, optical drive (i.e., Blueray, CD ROM/RAM/Recordable (R)/ and/or the like. ReWritable (RW), DVD R/RW, HD DVD R/RW etc.); an 0187 Peripheral devices 612, such as other components of array of devices (e.g., Redundant Array of Independent Disks the MR system, including signal generators in communica (RAID)): solid state memory devices (USB memory, solid tion with RF coils, receivers in communication with RF coils, state drives (SSD), etc.); other processor-readable storage the gradient coil system, main magnet system and the like mediums; and/or other devices of the like. Thus, a computer may be connected and/or communicate to I/O and/or other systemization generally requires and makes use of memory. facilities of the like Such as network interfaces, storage inter (0191 Component Collection faces, directly to the interface bus, system bus, the CPU, 0.192 The memory 629 may contain a collection of pro and/or the like. Peripheral devices may be external, internal gram and/or database components and/or data such as, but not and/or part of the MKTTM controller. Peripheral devices may limited to: operating system component(s) 615 (operating also include: antenna, audio devices (e.g., line-in, line-out, system); information server component(s) 616 (information microphone input, speakers, etc.), cameras (e.g., still, video, server); user interface component(s) 617 (user interface); webcam, etc.), dongles (e.g., for copy protection, ensuring Web browser component(s) 618 (Web browser); database(s) secure transactions with a digital signature, and/or the like), 619; mail server component(s) 621; mail client component(s) external processors (for added capabilities; e.g., crypto 622; cryptographic server component(s) 620 (cryptographic devices 628), force-feedback devices (e.g., vibrating motors), server) and/or the like (i.e., collectively a component collec network interfaces, printers, scanners, storage devices, trans tion). These components may be stored and accessed from the ceivers (e.g., cellular, GPS, etc.), video devices (e.g., goggles storage devices and/or from Storage devices accessible for functional imaging, for example, monitors, etc.), video through an interface bus. Although non-conventional pro US 2014/0285.191 A1 Sep. 25, 2014 gram components such as those in the component collection, ence Leveraging Extensions (SIMPLE), open XML-based typically, are stored in a local storage device 614, they may Extensible Messaging and Presence Protocol (XMPP) (i.e., also be loaded and/or stored in memory Such as: peripheral Jabber or Open Mobile Alliance's (OMAs) Instant Messag devices, RAM, remote storage facilities through a communi ing and Presence Service (IMPS)), Yahoo! Instant Messenger cations network, ROM, various forms of memory, and/or the Service, and/or the like. The information server provides like. results in the form of Web pages to Web browsers, and allows (0193 Operating System for the manipulated generation of the Web pages through 0194 The operating system component 615 is an execut interaction with other program components. After a Domain able program component facilitating the operation of the Name System (DNS) resolution portion of an HTTP request MKTTM controller. Typically, the operating system facilitates is resolved to a particular information server, the information access of I/O, network interfaces, peripheral devices, storage server resolves requests for information at specified locations devices, and/or the like. The operating system may be a highly on the MKTTM controller based on the remainder of the HTTP fault tolerant, Scalable, and secure system Such as: Apple request. For example, a request Such as http://123.124.125. Macintosh OS X (Server); AT&T Plan 9: Be OS: Unix and 126/myInformation.html might have the IP portion of the Unix-like system distributions (such as AT&T's UNIX: Berk request “123.124.125.126 resolved by a DNS server to an ley Software Distribution (BSD) variations such as FreeBSD, information server at that IP address; that information server NetBSD, OpenBSD, and/or the like; Linux distributions such might in turn further parse the http request for the “/myInfor as Red Hat, Ubuntu, and/or the like); and/or the like operating mation.html portion of the request and resolve it to a location systems. However, more limited and/or less secure operating in memory containing the information “my Information. systems also may be employed Such as Apple Macintosh OS, html. Additionally, other information serving protocols may IBM OS/2, Microsoft DOS, Microsoft Windows 2000/2003/ be employed across various ports, e.g., FTP communications 3.1/95/98/CE/Millenium/NT/Vista/XP (Server), Palm OS, across port 21, and/or the like. An information server may and/or the like. An operating system may communicate to communicate to and/or with other components in a compo and/or with other components in a component collection, nent collection, including itself, and/or facilities of the like. including itself, and/or the like. Most frequently, the operat Most frequently, the information server communicates with ing system communicates with other program components, the MKTTM database 619, operating systems, other program user interfaces, and/or the like. For example, the operating components, user interfaces, Web browsers, and/or the like. system may contain, communicate, generate, obtain, and/or (0197) Access to the MKTTM database may be achieved provide program component, System, user, and/or data com through a number of database bridge mechanisms such as munications, requests, and/or responses. The operating sys through scripting languages as enumerated below (e.g., CGI) tem, once executed by the CPU, may enable the interaction and through inter-application communication channels as with communications networks, data, I/O, peripheral devices, enumerated below (e.g., CORBA, WebObjects, etc.). Any program components, memory, user input devices, and/or the data requests through a Web browser are parsed through the like. The operating system may provide communications pro bridge mechanism into appropriate grammars as required by tocols that allow the MKTTM controller to communicate with the MKTTM. In one embodiment, the information server other entities through a communications network 613. Vari would provide a Web form accessible by a Web browser. ous communication protocols may be used by the MKTTM Entries made into supplied fields in the Web form are tagged controller as a Subcarrier transport mechanism for interac as having been entered into the particular fields, and parsed as tion, such as, but not limited to: multicast, TCP/IP, UDP, such. The entered terms are then passed along with the field unicast, and/or the like. tags, which act to instruct the parser to generate queries (0195 Information Server directed to appropriate tables and/or fields. In one embodi 0196. An information server component 616 is a stored ment, the parser may generate queries in standard SQL by program component that is executed by a CPU. The informa instantiating a search string with the proper join? select com tion server may be a conventional Internet information server mands based on the tagged text entries, wherein the resulting such as, but not limited to Apache Software Foundations command is provided over the bridge mechanism to the Apache, Microsoft's Internet Information Server, and/or the MKTTM as a query. Upon generating query results from the like. The information server may allow for the execution of query, the results are passed over the bridge mechanism, and program components through facilities such as Active Server may be parsed for formatting and generation of a new results Page (ASP), ActiveX, (ANSI) (Objective-) C (++), C# and/or Web page by the bridge mechanism. Such a new results Web .NET, Common Gateway Interface (CGI) scripts, dynamic page is then provided to the information server, which may (D) hypertext markup language (HTML), FLASH. Java, supply it to the requesting Web browser. JavaScript, Practical Extraction Report Language (PERL), 0198 Also, an information server may contain, commu Hypertext Pre-Processor (PHP), pipes, Python, wireless nicate, generate, obtain, and/or provide program component, application protocol (WAP), WebObjects, and/or the like. The system, user, and/or data communications, requests, and/or information server may support secure communications pro responses. tocols such as, but not limited to, File Transfer Protocol 0199. User Interface (FTP): HyperText Transfer Protocol (HTTP): Secure Hyper 0200 Computer interfaces in some respects are similar to text Transfer Protocol (HTTPS), Secure Socket Layer (SSL), automobile operation interfaces. Automobile operation inter messaging protocols (e.g., America Online (AOL) Instant face elements such as steering wheels, gearshifts, and speed Messenger (AIM), Application Exchange (APEX), ICO, ometers facilitate the access, operation, and display of auto Internet Relay Chat (IRC), Microsoft Network (MSN) Mes mobile resources, and status. Computer interaction interface senger Service, Presence and Instant Messaging Protocol elements such as check boxes, cursors, menus, Scrollers, and (PRIM), Internet Engineering Task Force's (IETFs) Session windows (collectively and commonly referred to as widgets) Initiation Protocol (SIP), SIP for Instant Messaging and Pres similarly facilitate the access, capabilities, operation, and US 2014/0285.191 A1 Sep. 25, 2014 22 display of data and computer hardware and operating system limited to sendmail, Microsoft Exchange, and/or the like. The resources, and status. Operation interfaces are commonly mail server may allow for the execution of program compo called user interfaces. Graphical user interfaces (GUIs) such nents through facilities such as ASP. ActiveX, (ANSI) (Ob as the Apple Macintosh Operating System’s Aqua, IBM's jective-) C (++), C# and/or .NET, CGI scripts, Java, JavaS OS/2, Microsoft's Windows 2000/2003/3.1/95/98/CE/Mille cript, PERL, PHP pipes, Python, WebObjects, and/or the like. nium/NT/XP/Vista/7 (i.e., Aero), Unix's X-Windows (e.g., The mail server may support communications protocols such which may include additional Unix graphic interface libraries as, but not limited to: Internet message access protocol and layers such as K Desktop Environment (KDE), mythTV (IMAP), Messaging Application Programming Interface and GNU Network Object Model Environment (GNOME)), (MAPI)/Microsoft Exchange, post office protocol (POP3), web interface libraries (e.g., ActiveX, AJAX, (D)HTML, simple mail transfer protocol (SMTP), and/or the like. The FLASH. Java, JavaScript, etc. interface libraries such as, but mail server can route, forward, and process incoming and not limited to, Dojo.jQuery(UI), MooTools, Prototype, scrip outgoing mail messages that have been sent, relayed and/or taculo.us, SWFObject, Yahoo! User Interface, any of which otherwise traversing through and/or to the MKTTM. may be used and) provide a baseline and means of accessing (0206. Access to the MKTTM mail may beachieved through and displaying information graphically to users. a number of APIs offered by the individual Web server com 0201 A user interface component 617 is a stored program ponents and/or the operating system. component that is executed by a CPU. The user interface may 0207 Also, a mail server may contain, communicate, gen be a conventional graphic user interface as provided by, with, erate, obtain, and/or provide program component, system, and/or atop operating systems and/or operating environments user, and/or data communications, requests, information, Such as already discussed. The user interface may allow for and/or responses. the display, execution, interaction, manipulation, and/or 0208. Mail Client operation of program components and/or system facilities 0209. A mail client component 622 is a stored program through textual and/or graphical facilities. The user interface component that is executed by a CPU 603. The mail client provides a facility through which users may affect, interact, may be a conventional mail viewing application Such as and/or operate a computer system. A user interface may com Apple Mail, Microsoft Entourage, Microsoft Outlook, municate to and/or with other components in a component Microsoft Outlook Express, Mozilla, Thunderbird, and/or the collection, including itself, and/or facilities of the like. Most like. Mail clients may support a number of transfer protocols, frequently, the user interface communicates with operating such as: IMAP, Microsoft Exchange, POP3, SMTP, and/or systems, other program components, and/or the like. The user the like. A mail client may communicate to and/or with other interface may contain, communicate, generate, obtain, and/or components in a component collection, including itself, and/ provide program component, system, user, and/or data com or facilities of the like. Most frequently, the mail client com munications, requests, and/or responses. municates with mail servers, operating systems, other mail 0202 Web Browser clients, and/or the like; e.g., it may contain, communicate, 0203 A Web browser component 618 is a stored program generate, obtain, and/or provide program component, system, component that is executed by a CPU. The Web browser may user, and/or data communications, requests, information, be a conventional hypertext viewing application Such as and/or responses. Generally, the mail client provides a facility Microsoft Internet Explorer or Netscape Navigator. Secure to compose and transmit electronic mail messages. Web browsing may be supplied with 128 bit (or greater) 0210 Cryptographic Server encryption by way of HTTPS, SSL, and/or the like. Web 0211 A cryptographic server component 620 is a stored browsers allowing for the execution of program components program component that is executed by a CPU 603, crypto through facilities such as ActiveX, AJAX, (D)HTML, graphic processor 626, cryptographic processor interface FLASH. Java, JavaScript, web browser plug-in APIs (e.g., 627, cryptographic processor device 628, and/or the like. FireFox, Safari Plug-in, and/or the like APIs), and/or the like. Cryptographic processor interfaces will allow for expedition Web browsers and like information access tools may be inte of encryption and/or decryption requests by the crypto grated into PDAs, cellular telephones, and/or other mobile graphic component; however, the cryptographic component, devices. A Web browser may communicate to and/or with alternatively, may run on a conventional CPU. The crypto other components in a component collection, including itself. graphic component allows for the encryption and/or decryp and/or facilities of the like. Most frequently, the Web browser tion of provided data. The cryptographic component allows communicates with information servers, operating systems, for both symmetric and asymmetric (e.g., Pretty Good Pro integrated program components (e.g., plug-ins), and/or the tection (PGP)) encryption and/or decryption. The crypto like; e.g., it may contain, communicate, generate, obtain, graphic component may employ cryptographic techniques and/or provide program component, system, user, and/or data such as, but not limited to: digital certificates (e.g., X.509 communications, requests, and/or responses. Of course, in authentication framework), digital signatures, dual signa place of a Web browser and information server, a combined tures, enveloping, password access protection, public key application may be developed to perform similar functions of management, and/or the like. The cryptographic component both. The combined application would similarly affect the will facilitate numerous (encryption and/or decryption) Secu obtaining and the provision of information to users, user rity protocols such as, but not limited to: checksum, Data agents, and/or the like from the MKTTM enabled nodes. The Encryption Standard (DES), Elliptical Curve Encryption combined application may be nugatory on systems employ (ECC), International Data Encryption Algorithm (IDEA), ing standard Web browsers. Message Digest 5 (MD5, which is a one way hash function), 0204 Mail Server passwords, Rivest Cipher (RC5), Rijndael, RSA (which is an 0205. A mail server component 621 is a stored program Internet encryption and authentication system that uses an component that is executed by a CPU 603. The mail server algorithm developed in 1977 by Ron Rivest, Adi Shamir, and may be a conventional Internet mail server Such as, but not Leonard Adleman), Secure Hash Algorithm (SHA), Secure US 2014/0285.191 A1 Sep. 25, 2014

Socket Layer (SSL), Secure Hypertext Transfer Protocol mented as a mix of data structures, objects, and relational (HTTPS), and/or the like. Employing such encryption secu structures. Databases may be consolidated and/or distributed rity protocols, the MKTTM may encrypt all incoming and/or in countless variations through standard data processing tech outgoing communications and may serve as node within a niques. Portions of databases, e.g., tables, may be exported virtual private network (VPN) with a wider communications and/or imported and thus decentralized and/or integrated. network. The cryptographic component facilitates the pro 0215. In one embodiment, the database component 619 cess of “security authorization' whereby access to a resource includes several tables 619aj. A Users (e.g., operators and is inhibited by a security protocol wherein the cryptographic physicians) table 619 a may include fields such as, but not component effects authorized access to the secured resource. limited to: user id., SSn, dob, first name, last name, age, In addition, the cryptographic component may provide state, address firstline, address secondline, Zipcode, device unique identifiers of content, e.g., employing and MD5 hash S list, contact info, contact type, alt contact info, alt con to obtain a unique signature for an digital audio file. A cryp tact type, and/or the like to refer to any type of enterable data tographic component may communicate to and/or with other or selections discussed herein. The Users table may support components in a component collection, including itself, and/ and/or track multiple entity accounts. A Clients table 619b or facilities of the like. The cryptographic component Sup may include fields such as, but not limited to: user id, client ports encryption schemes allowing for the secure transmis id, client ip, client type, client model, operating system, sion of information across a communications network to os Version, app installed flag, and/or the like. An AppStable enable the MKTTM component to engage in secure transac 619.c may include fields such as, but not limited to: app ID, tions if so desired. The cryptographic component facilitates app name, app type, OS compatibilities list, version, the secure accessing of resources on the MKTTM and facili timestamp, developer ID, and/or the like. A Patients table for tates the access of secured resources on remote systems; i.e., patients associated with an entity administering the magnetic it may act as a client and/or server of secured resources. Most resonance system 619d may include fields such as, but not frequently, the cryptographic component communicates with limited to: patient id, patient name, patient address, ip ad information servers, operating systems, other program com dress, mac address, auth key, port num, Security settings ponents, and/or the like. The cryptographic component may list, and/or the like. An MR Studies table 619e may include contain, communicate, generate, obtain, and/or provide pro fields Such as, but not limited to: Study id, study name, Secu gram component, system, user, and/or data communications, rity settings list, study parameters, rf sequences, gradient requests, and/or responses. sequences, coil selection, imaging mode, and/or the like. An 0212. The MKTTM Database RF sequences table 619f including a plurality of different rf 0213. The MKTTM database component 619 may be pulse sequences may include fields such as, but not limited to: embodied in a database and its stored data. The database is a sequence type, sequence id, tip angle, coil selection, pow stored program component, which is executed by the CPU: er level, and/or the like. A gradient sequences table 619g may the stored program component portion configuring the CPU include fields relating to different gradient field sequences to process the stored data. The database may be a conven Such as, but not limited to: sequence id. GX, Gy, GZ, Gxy, tional, fault tolerant, relational, Scalable, secure database GXZ, GyZ, GXyZ, field strength, time duration, and/or the such as Oracle or Sybase. Relational databases are an exten like. A raw MR data table 619h may include fields such as, but sion of a flat file. Relational databases consist of a series of not limited to: Study id, time stamp, file size, patient id, related tables. The tables are interconnected via a key field. rf sequence, body part imaged, slice id, and/or the like. A Use of the key field allows the combination of the tables by Images table 619i may include fields such as, but not limited indexing against the key field; i.e., the key fields act as dimen to: image id, study id, file size, patient id, time stamp, set sional pivot points for combining information from various tings, and/or the like. A Payment Legers table 619i may tables. Relationships generally identify links maintained include fields such as, but not limited to: request id, times between tables by matching primary keys. Primary keys rep tamp, payment amount, batch id, transaction id, clear flag, resent fields that uniquely identify the rows of a table in a deposit account, transaction Summary, patient name, relational database. More precisely, they uniquely identify patient account, and/or the like. rows of a table on the “one side of a one-to-many relation 0216. In one embodiment, user programs may contain ship. various user interface primitives, which may serve to update 0214) Alternatively, the MKTTM database may be imple the MKTTM platform. Also, various accounts may require mented using various standard data-structures, such as an custom database tables depending upon the environments and array, hash, (linked) list, struct, structured text file (e.g., the types of clients the MKTTM system may need to serve. It XML), table, and/or the like. Such data-structures may be should be noted that any unique fields may be designated as a stored in memory and/or in (structured) files. In another alter key field throughout. In an alternative embodiment, these native, an object-oriented database may be used, such as tables have been decentralized into their own databases and Frontier, ObjectStore, Poet, Zope, and/or the like. Object their respective database controllers (i.e., individual database databases can include a number of object collections that are controllers for each of the above tables). Employing standard grouped and/or linked together by common attributes; they data processing techniques, one may further distribute the may be related to other object collections by some common databases over several computer systemizations and/or stor attributes. Object-oriented databases perform similarly to age devices. Similarly, configurations of the decentralized relational databases with the exception that objects are not database controllers may be varied by consolidating and/or just pieces of data but may have other types of functionality distributing the various database components 619a-i. The encapsulated within a given object. If the MKTTM database is MKTTM system may be configured to keep track of various implemented as a data-structure, the use of the MKTTM data settings, inputs, and parameters via database controllers. base 619 may be integrated into another component such as 0217. The MKTTM database may communicate to and/or the MKTTM component 635. Also, the database may be imple with other components in a component collection, including US 2014/0285.191 A1 Sep. 25, 2014 24 itself, and/or facilities of the like. Most frequently, the gram component collection may be instantiated on a single MKTTM database communicates with the MKTTM compo node, and/or across numerous nodes to improve performance nent, other program components, and/or the like. The data through load-balancing and/or data-processing techniques. base may contain, retain, and provide information regarding Furthermore, single instances may also be distributed across other nodes and data. multiple controllers and/or storage devices; e.g., databases. 0218. The MKTTM Components All program component instances and controllers working in 0219. The MKTTM component 635 is a stored program concert may do so through standard data processing commu component that is executed by a CPU. In one embodiment, nication techniques. the MKTTM component incorporates any and/or all combina 0225. The configuration of the MKTTM controller will tions of the aspects of the MKTTM systems discussed in the depend on the context of system deployment. Factors such as, previous figures. As such, the MKTTM component affects but not limited to, the budget, capacity, location, and/or use of accessing, obtaining and the provision of information, Ser the underlying hardware resources may affect deployment vices, transactions, and/or the like across various communi requirements and configuration. Regardless of if the configu cations networks. ration results in more consolidated and/or integrated program 0220. The MKTTM component may transform raw data components, results in a more distributed series of program collected by the magnetic resonance system into at least one components, and/or results in some combination between a of (i) an image, (ii) dynamic flow data, (iii) perfusion data, consolidated and distributed configuration, data may be com (iii) spectroscopic identity of chemical species, (iv) physi municated, obtained, and/or provided. Instances of compo ological data, or (V) metabolic data, among other things. In nents consolidated into a common code base from the pro one embodiment, the MKTTM component 635 takes inputs gram component collection may communicate, obtain, and/ (e.g., digitized representations of Mxy signals produced by or provide data. This may be accomplished through intra RD or SR pulses, and transforms the inputs via various com application data processing communication techniques such ponents of the system, into outputs (e.g., (i) an image, (ii) as, but not limited to: data referencing (e.g., pointers), internal dynamic flow data, (iii) perfusion data, (iii) spectroscopic messaging, object instance variable communication, shared identity of chemical species, (iv) physiological data, or (V) memory space, variable passing, and/or the like. metabolic data, among other things). 0226. If component collection components are discrete, 0221) The MKTTM component enabling access of infor separate, and/or external to one another, then communicating, mation between nodes may be developed by employing stan obtaining, and/or providing data with and/or to other compo dard development tools and languages such as, but not limited nent components may be accomplished through inter-appli to: Apache components, Assembly, ActiveX, binary cation data processing communication techniques such as, executables, (ANSI) (Objective-) C (++), C# and/or .NET, but not limited to: Application Program Interfaces (API) database adapters, CGI scripts, Java, JavaScript, mapping information passage; (distributed) Component Object Model tools, procedural and object oriented development tools, ((D)COM), (Distributed) Object Linking and Embedding PERL, PHP, Python, shell scripts, SQL commands, web ((D)OLE), and/or the like), Common Object Request Broker application server extensions, web development environ Architecture (CORBA), Jini local and remote application ments and libraries (e.g., Microsoft's ActiveX: Adobe AIR, program interfaces, JavaScript Object Notation (JSON). FLEX & FLASH: AJAX: (D)HTML; Dojo, Java: JavaScript: Remote Method Invocation (RMI), SOAP process pipes, jQuery(UI); MooTools; Prototype; script.aculo.us; Simple shared files, and/or the like. Messages sent between discrete Object Access Protocol (SOAP); SWFObject: Yahoo! User component components for inter-application communication Interface; and/or the like), WebObjects, and/or the like. In one or within memory spaces of a singular component for intra embodiment, the MKTTM server employs a cryptographic application communication may be facilitated through the server to encrypt and decrypt communications. The MKTTM creation and parsing of a grammar. A grammar may be devel component may communicate to and/or with other compo oped by using development tools such as lex, yacc, XML, nents in a component collection, including itself, and/or and/or the like, which allow for grammar generation and facilities of the like. Most frequently, the MKTTM component parsing capabilities, which in turn may form the basis of communicates with the MKTTM database, operating systems, communication messages within and between components. other program components, and/or the like. The MKTTM may 0227 For example, a grammar may be arranged to recog contain, communicate, generate, obtain, and/or provide pro nize the tokens of an HTTP post command, e.g.: gram component, system, user, and/or data communications, 0228 w8c-post http://. . . Value1 requests, and/or responses. 0229 where Value1 is discerned as being a parameter 0222 Distributed MKTTM Embodiments because "http:/7 is part of the grammar Syntax, and what 0223. The structure and/or operation of any of the MKTTM follows is considered part of the post value. Similarly, with node controller components may be combined, consolidated, such a grammar, a variable “Value1 may be inserted into an and/or distributed in any number of ways to facilitate devel "http:// post command and then sent. The grammar syntax opment and/or deployment. Similarly, the component collec itself may be presented as structured data that is interpreted tion may be combined in any number of ways to facilitate and/or otherwise used to generate the parsing mechanism deployment and/or development. To accomplish this, one (e.g., a syntax description text file as processed by lex, yacc, may integrate the components into a common code base or in etc.). Also, once the parsing mechanism is generated and/or a facility that can dynamically load the components on instantiated, it itself may process and/or parse structured data demand in an integrated fashion. Such as, but not limited to: character (e.g., tab) delineated text, 0224. The component collection may be consolidated and/ HTML, structured text streams, XML, and/or the like struc or distributed in countless variations through standard data tured data. In another embodiment, inter-application data processing and/or development techniques. Multiple processing protocols themselves may have integrated and/or instances of any one of the program components in the pro readily available parsers (e.g., JSON, SOAP and/or like pars US 2014/0285.191 A1 Sep. 25, 2014

ers) that may be employed to parse (e.g., communications) TUSES, METHODS AND SYSTEMS (including the Cover data. Further, the parsing grammar may be used beyond mes Page, Title, Headings, Field, Background, Summary, Brief sage parsing, but may also be used to parse: databases, data Description of the Drawings, Detailed Description, Claims, collections, data stores, structured data, and/or the like. Abstract, Figures, Appendices and/or otherwise) shows by Again, the desired configuration will depend upon the con way of illustration various embodiments in which the dis text, environment, and requirements of system deployment. closed embodiments may be practiced. The advantages and 0230. For example, in some implementations, the MKTTM features of the application are of a representative sample of controller may be executing a PHP script implementing a embodiments only, and are not exhaustive and/or exclusive. Secure Sockets Layer (“SSL) socket server via the informa They are presented only to assist in understanding and teach tion server, which listens to incoming communications on a the claimed principles. It should be understood that they are serverport to which a client may send data, e.g., data encoded not representative of all disclosed embodiments. As such, in JSON format. Upon identifying an incoming communica certain aspects of the disclosure have not been discussed tion, the PHP script may read the incoming message from the herein. That alternate embodiments may not have been pre client device, parse the received JSON-encoded text data to sented for a specific portion of the disclosure or that further extract information from the JSON-encoded text data into undescribed alternate embodiments may be available for a PHP script variables, and store the data (e.g., client identify portion is not to be considered a disclaimer of those alternate ing information, etc.) and/or extracted information in a rela embodiments. It will be appreciated that many of those unde tional database accessible using the Structured Query Lan scribed embodiments incorporate the same principles of the guage (SQL). An exemplary listing, written Substantially in disclosure and others are equivalent. Thus, it is to be under the form of PHP/SQL commands, to accept JSON-encoded stood that other embodiments may be utilized and functional, input data from a client device via a SSL connection, parse the logical, organizational, structural and/or topological modifi data to extract variables, and store the data to a database, is cations may be made without departing from the scope and/or provided below: spirit of the disclosure. As such, all examples and/or embodi ments are deemed to be non-limiting throughout this disclo Sure. Also, no inference should be drawn regarding those file additional applications, continuations, continuations in part, divisions, and/or the like thereof. As such, it should be Also, the following resources may be used to provide understood that advantages, embodiments, examples, func example embodiments regarding SOAP parser implementa tional, features, logical, organizational, structural, topologi tion: cal, and/or other aspects of the disclosure are not to be con 0231 http://www.xav.com/perl/site/lib/SOAP/Parser. sidered limitations on the disclosure as defined by the claims html or limitations on equivalents to the claims. It is to be under 0232 http://publib.boulder.ibm.com/infocenter/tivi stood that, depending on the particular needs and/or charac help/v2r1/index.jsp?topic=/com.ibm. IBMDI.doc/refer teristics of a MKTTM individual and/or enterprise user, data enceguide295.htm base configuration and/or relational model, data type, data and other parser implementations: transmission and/or network framework, syntax structure, 0233 http://publib.boulder.ibm.com/infocenter/tivi and/or the like, various embodiments of the MKTTM may be help/v2r1/index.jsp?topic=/com.ibm. IBMDI.doc/refer implemented that enable a great deal of flexibility and cus enceguide259.htm tomization. all of which are hereby expressly incorporated by reference. 0235 All statements herein reciting principles, aspects, 0234. In order to address various issues and advance the and embodiments of the disclosure, as well as specific art, the entirety of this application for MKTTM APPARA examples thereof, are intended to encompass both structural US 2014/0285.191 A1 Sep. 25, 2014 26 and functional equivalents thereof. Additionally, it is intended f) collecting three dimensional spatial data for a set of that Such equivalents include both currently known equiva nuclei of interest from at least one of the (i) sample or lents as well as equivalents developed in the future, i.e., any subject, and (ii) the SSR; and elements developed that perform the same function, regard g) optionally collecting three dimensional spatial data for a less of structure. set of nuclei of interest from at least one of the (i) sample 0236. Descriptions herein of circuitry and method steps or subject, and (ii) the SSR; and computer programs represent conceptual embodiments 2. The method of claim 1, wherein: of illustrative circuitry and software embodying the prin a) the method further comprises administering a beneficial ciples of the disclosed embodiments. Thus the functions of agent including a biomarker to the Subject; and the various elements shown and described herein may be c) the beneficial agent includes a molecule that has been provided through the use of dedicated hardware as well as combined with the biomarker. hardware capable of executing software in association with appropriate Software as set forth herein. 3. The method of claim 2, wherein the biomarker includes 0237. In the disclosure hereof any element expressed as a at least one of (i) “F (ii) 'H, (iii) C, (iv) 'N, (v) P. means for performing a specified function is intended to 4. The method of claim 2, wherein the molecule is a phar encompass any way of performing that function including, maceutical is for human use. for example, a) a combination of circuit elements and asso 5. The method of claim 2, wherein the molecule is a phar ciated hardware which perform that function or b) software in maceutical is for veterinary use. any form, including, therefore, firmware, microcode or the 6. The method of claim 2, wherein the molecule is at least like as set forth herein, combined with appropriate circuitry one of (i) a cosmecuetical, (ii) a neutraceutical, (iii) an agri for executing that software to perform the function. Appli cultural chemical, (iv) a protein, and (v) a carbohydrate. cants thus regard any means which can provide those func 7. The method of claim 2, wherein the biomarker is present tionalities as equivalent to those shown herein. Similarly, it in a chemical group that is Substituted for a methyl group on will be appreciated that the system and process flows the molecule, wherein the chemical group is selected from the described herein represent various processes which may be group consisting of (i) CF, (ii) CHF, and (iii) CHF. Substantially represented in computer-readable media and so 8. The method of claim 1, further comprising processing executed by a computer or processor, whether or not such information obtained from a plurality of pulses of RF mag computer or processor is explicitly shown. Moreover, the netization to produce at least one of (i) an image, (ii) dynamic various processes can be understood as representing not only flow data, (iii) perfusion data, (iii) spectroscopic identity of processing and/or other functions but, alternatively, as blocks chemical species, (iv) physiological data, or (V) metabolic of program code that carry out such processing or functions. data. 0238. The methods, systems, computer programs and 9. A method for performing magnetic resonance spectro mobile devices of the present disclosure, as described above Scopic imaging comprising: and shown in the drawings, among other things, provide for a) providing a magnetic resonance device including (i) a improved magnetic resonance methods, systems and machine main magnet for providing a background magnetic field readable programs for carrying out the same. It will be appar along a first direction, (ii) at least one radio-frequency ent to those skilled in the art that various modifications and coil, and (iii) at least one gradient coil that can be con variations can be made in the devices, methods, Software trolled to define a region of interest; programs and mobile devices of the present disclosure with b) positioning a Supplemental spin reservoir within a field out departing from the spirit or scope of the disclosure. Thus, of view of the at least one resonant coil, the Supplemental it is intended that the present disclosure include modifications spin reservoir (SSR) including a plurality of molecules: and variations that are within the scope of the subject disclo Sure and equivalents. c) introducing a sample or subject to be studied into the What is claimed is: region of interest; 1. A method for performing magnetic resonance spectro d) introducing RF pulses into the sample or subject; Scopic imaging comprising: e) adjusting at least one of (i) the circuitry of the at least one a) providing a magnetic resonance device including (i) a radio frequency coil, and (ii) the contents of the SSR in main magnet for providing a background magnetic field order to induce electromagnetic feedback between the along a first direction, (ii) at least one radio-frequency nuclear magnetization of the set of nuclei of interest and coil, and (iii) at least one gradient coil that can be con the at least one radio frequency coil to cause the vector trolled to define a region of interest; direction of the nuclear magnetization of the set of b) positioning a Supplemental spin reservoir within a field nuclei of interest to rotate to a desired angle; of view of the at least one resonant coil, the Supplemental f) analyzing the pulse of transverse magnetization resulting spin reservoir (SSR) including a plurality of molecules: from the rotation of the magnetization in the previous c) introducing a sample or subject to be studied into the step; and region of interest; g) optionally repeating steps a-fto improve at least one of d) introducing RF pulses into the sample or subject; i) image intensity and ii) spectral resolution. e) adjusting at least one of (i) the circuitry of the at least one 10. The method of claim 1, wherein the at least one reso radio frequency coil, and (ii) the contents of the SSR in nant coil is configured to amplify and/or phase adjust the order to induce electromagnetic feedback between the electromagnetic feedback received from nuclei in the set of nuclear magnetization of the set of nuclei of interest and nuclei of interest. the at least one radio frequency coil to cause the vector 11. The method of claim 1, further comprising adjusting direction of the nuclear magnetization of the set of the at least one RF coil to intensify electromagnetic feedback nuclei of interest to 90 degrees by adjusting at least one parameter of the feedback field. US 2014/0285.191 A1 Sep. 25, 2014 27

12. The method of claim 9, wherein electromagnetic feed back is induced at least in part by Substantially eliminating the presence of a gradient magnetic field in the at least one region of interest. 13. The method of claim 9, wherein the region of interest includes at least one voxel, and the at least one gradient coil is adapted and configured to apply a magnetic field gradient in at least one of three mutually orthogonal directions. 14. The method of claim 1, wherein the method further comprises administering a beneficial agent including FASLODEX (fulvestrant), NEXAVAR (Sorafenib) STI VARGA (regorafenib), a non-radioactive form of AMYVID (fluorbetapir), BANZEL (rufinamide), ZELBORAF (vemu rafenib) or 5-fluorouracil to the subject before imaging. k k k k k