Abstract:
A system and method performing a medical imaging process includes arranging a subject to receive an exogenously administered free radical probe, performing an Overhauser-enhanced MRI (OMRI) imaging process to acquire data from the subject, and reconstructing the data to generate a report indicating a spatial distribution of free radicals in the subject.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is based on, claims priority to, and incorporates herein by reference, U.S. Provisional Application Ser. No. 61/953,452, filed Mar. 14, 2014, and entitled “SYSTEM AND METHOD FOR IMAGING FREE RADICALS USING MAGNETIC RESONANCE IMAGING SYSTEMS AND PROBES.” 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH 
       [0002]    This invention was made with government support under W81XWH-11-2-076 awarded by the Department of Defense. The government has certain rights in the invention. 
     
    
     BACKGROUND 
       [0003]    The present disclosure relates to systems and methods for the invention is magnetic resonance imaging (MRI). More particularly, the present disclosure provides systems and methods for imaging free radicals using MRI and probes. 
         [0004]    When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B 0 ), the individual magnetic moments of the excited nuclei in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B 1 ) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, M z , may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetic moment M t . A signal is emitted by the excited nuclei or “spins”, after the excitation signal B 1  is terminated, and this signal may be received and processed to form an image. 
         [0005]    When utilizing these “MR” signals to produce images, magnetic field gradients (G x , G y , and G z ) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received MR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques. 
         [0006]    Acute reperfusion therapies have changed ischemic stroke care, but treatments are limited because of a short therapeutic window owing to the risk of reperfusion injury and hemorrhage. Detection of early and mild blood-brain barrier (BBB) disruption is an unmet need in acute stroke diagnosis. Although contrast from relaxation-based MRI contrast agents such as Gd-DTPA is correlated with hemorrhagic transformation of an infarct, it is not sensitive enough to probe more mild BBB disruption. 
         [0007]    Thus, further developments are necessary to meet clinical needs. 
       SUMMARY 
       [0008]    The present invention overcomes the aforementioned drawbacks by providing a system and method for Overhauser-enhanced MRI (OMRI) in conjunction with an injected stable free radical. 
         [0009]    In accordance with one aspect of the disclosure, a magnetic resonance imaging (MRI) system is disclosed that is configured to perform an imaging process of a subject having received an exogenously administered free radical probe. The system includes a magnet system configured to generate a static magnetic field about at least a region of interest (ROI) of the subject arranged in the MRI system and at least one gradient coil configured to establish at least one magnetic gradient field with respect to the static magnetic field. The system also includes a radio frequency (RF) system configured to deliver excitation pulses to the subject and a computer system. The computer system is configured to control the at least one gradient coil and the RF system to perform a magnetic resonance (MR) imaging pulse sequence and, while performing the MR pulse sequence, perform electron spin resonance (ESR) pulses. The computer system is further configured to acquire data corresponding to signals from the subject having received an exogenously administered free radical probe excited by the MR pulse sequence and the ESR pulses and reconstruct, from the data, at least one anatomical image of the subject and spatially distributed free radicals within the subject relative to the anatomical image. 
         [0010]    In accordance with another aspect of the disclosure, a method is provided for performing a medical imaging process. The method includes arranging a subject to receive an exogenously administered free radical probe and performing an Overhauser-enhanced magnetic resonance imaging (OMRI) process to acquire data from the subject. The method also includes reconstructing the data to generate a report indicating a spatial distribution of free radicals in the subject. 
         [0011]    The foregoing and other advantages of the invention will appear from the following description. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  is a block diagram of an MRI system. 
           [0013]      FIG. 2  is a block diagram of an RF system of an MRI system. 
           [0014]      FIG. 3  is a picture of a low-field MRI (IfMRI) system in accordance with the present disclosure. 
           [0015]      FIG. 4  is a picture of a probe for OMRI in accordance with the present disclosure. 
           [0016]      FIG. 5  is a series of images including a photo of a TEMPOL concentration phantom and images thereof. 
           [0017]      FIG. 6  is a set of images showing OMRI magnitude and phase images acquired from a rat at 6.5 mT following 75 min right MCAO and 60 min reperfusion. Four coronal slices from 10 slice data set shown. OMRI (NA=10) imaging time was 195 seconds. Low-resolution anatomical MRI (NA=80) was acquired in the OMRI scanner at 6.5 mT with DNP pulses disabled. MRI imaging time was 17 min. All images, voxel size: 1.1×1.6×8 mm3, TE/TR: 18/36 ms, Matrix: 128 x 35×10 
       
    
    
     DETAILED DESCRIPTION 
       [0018]    Overhauser-enhanced MRI (OMRI) is a promising technique for imaging free radicals, and a recently developed fast high-resolution OMRI methodology (Sarracanie M et al. MRM 2013 DOI: 10.1002/mrm.24705, which is incorporated herein by reference in its entirety) offers new perspectives for the imaging of free radicals in living organisms. As will be described, the present disclosure provides a method to probe hyperacute BBB breakdown following ischemic stroke using OMRI in conjunction with an injected stable free radical. However, before discussing these systems and methods, a general discussion of MR systems is provided. 
         [0019]    Referring particularly now to  FIG. 1 , an example of a magnetic resonance imaging (MRI) system  100  is illustrated. The MRI system  100  includes an operator workstation  102 , which will typically include a display  104 , one or more input devices  106 , such as a keyboard and mouse, and a processor  108 . The processor  108  may include a commercially available programmable machine running a commercially available operating system. The operator workstation  102  provides the operator interface that enables scan prescriptions to be entered into the MRI system  100 . In general, the operator workstation  102  may be coupled to four servers: a pulse sequence server  110 ; a data acquisition server  112 ; a data processing server  114 ; and a data store server  116 . The operator workstation  102  and each server  110 ,  112 ,  114 , and  116  are connected to communicate with each other. For example, the servers  110 ,  112 ,  114 , and  116  may be connected via a communication system  117 , which may include any suitable network connection, whether wired, wireless, or a combination of both. As an example, the communication system  117  may include both proprietary or dedicated networks, as well as open networks, such as the internet. 
         [0020]    The pulse sequence server  110  functions in response to instructions downloaded from the operator workstation  102  to operate a gradient system  118  and a radiofrequency (“RF”) system  120 . Gradient waveforms necessary to perform the prescribed scan are produced and applied to the gradient system  118 , which excites gradient coils in an assembly  122  to produce the magnetic field gradients G x , G y , and G z  used for position encoding magnetic resonance signals. The gradient coil assembly  122  forms part of a magnet assembly  124  that includes a polarizing magnet  126  and a whole-body RF coil  128  and/or local coil, such as a head coil  129 . 
         [0021]    RF waveforms are applied by the RF system  120  to the RF coil  128 , or a separate local coil, such as the head coil  129 , in order to perform the prescribed magnetic resonance pulse sequence. Responsive magnetic resonance signals detected by the RF coil  128 , or a separate local coil, such as the head coil  129 , are received by the RF system  120 , where they are amplified, demodulated, filtered, and digitized under direction of commands produced by the pulse sequence server  110 . The RF system  120  includes an RF transmitter for producing a wide variety of RF pulses used in MRI pulse sequences. The RF transmitter is responsive to the scan prescription and direction from the pulse sequence server  110  to produce RF pulses of the desired frequency, phase, and pulse amplitude waveform. The generated RF pulses may be applied to the whole-body RF coil  128  or to one or more local coils or coil arrays, such as the head coil  129 . 
         [0022]    The RF system  120  also includes one or more RF receiver channels. Each RF receiver channel includes an RF preamplifier that amplifies the magnetic resonance signal received by the coil  128 / 129  to which it is connected, and a detector that detects and digitizes the I and Q quadrature components of the received magnetic resonance signal. The magnitude of the received magnetic resonance signal may, therefore, be determined at any sampled point by the square root of the sum of the squares of the I and Q components: 
         [0000]        M =√{square root over ( I   2   +Q   2 )}  (1)
 
         [0023]    and the phase of the received magnetic resonance signal may also be determined according to the following relationship: 
         [0000]    
       
         
           
             
               
                 
                   ϕ 
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                         tan 
                         
                           - 
                           1 
                         
                       
                        
                       
                         ( 
                         
                           Q 
                           I 
                         
                         ) 
                       
                     
                     . 
                   
                 
               
               
                 
                   ( 
                   2 
                   ) 
                 
               
             
           
         
       
     
         [0024]    The pulse sequence server  110  also optionally receives patient data from a physiological acquisition controller  130 . By way of example, the physiological acquisition controller  130  may receive signals from a number of different sensors connected to the patient, such as electrocardiograph (“ECG”) signals from electrodes, or respiratory signals from a respiratory bellows or other respiratory monitoring device. Such signals are typically used by the pulse sequence server  110  to synchronize, or “gate,” the performance of the scan with the subject&#39;s heart beat or respiration. 
         [0025]    The pulse sequence server  110  also connects to a scan room interface circuit  132  that receives signals from various sensors associated with the condition of the patient and the magnet system. It is also through the scan room interface circuit  132  that a patient positioning system  134  receives commands to move the patient to desired positions during the scan. 
         [0026]    The digitized magnetic resonance signal samples produced by the RF system  120  are received by the data acquisition server  112 . The data acquisition server  112  operates in response to instructions downloaded from the operator workstation  102  to receive the real-time magnetic resonance data and provide buffer storage, such that no data is lost by data overrun. In some scans, the data acquisition server  112  does little more than pass the acquired magnetic resonance data to the data processor server  114 . However, in scans that require information derived from acquired magnetic resonance data to control the further performance of the scan, the data acquisition server  112  is programmed to produce such information and convey it to the pulse sequence server  110 . For example, during prescans, magnetic resonance data is acquired and used to calibrate the pulse sequence performed by the pulse sequence server  110 . As another example, navigator signals may be acquired and used to adjust the operating parameters of the RF system  120  or the gradient system  118 , or to control the view order in which k-space is sampled. In still another example, the data acquisition server  112  may also be employed to process magnetic resonance signals used to detect the arrival of a contrast agent in a magnetic resonance angiography (MRA) scan. By way of example, the data acquisition server  112  acquires magnetic resonance data and processes it in real-time to produce information that is used to control the scan. 
         [0027]    The data processing server  114  receives magnetic resonance data from the data acquisition server  112  and processes it in accordance with instructions downloaded from the operator workstation  102 . Such processing may, for example, include one or more of the following: reconstructing two-dimensional or three-dimensional images by performing a Fourier transformation of raw k-space data; performing other image reconstruction algorithms, such as iterative or backprojection reconstruction algorithms; applying filters to raw k-space data or to reconstructed images; generating functional magnetic resonance images; calculating motion or flow images; and so on. 
         [0028]    Images reconstructed by the data processing server  114  are conveyed back to the operator workstation  102  where they are stored. Real-time images are stored in a data base memory cache (not shown in  FIG. 1 ), from which they may be output to operator display  112  or a display  136  that is located near the magnet assembly  124  for use by attending physicians. Batch mode images or selected real time images are stored in a host database on disc storage  138 . When such images have been reconstructed and transferred to storage, the data processing server  114  notifies the data store server  116  on the operator workstation  102 . The operator workstation  102  may be used by an operator to archive the images, produce films, or send the images via a network to other facilities. 
         [0029]    The MRI system  100  may also include one or more networked workstations  142 . By way of example, a networked workstation  142  may include a display  144 ; one or more input devices  146 , such as a keyboard and mouse; and a processor  148 . The networked workstation  142  may be located within the same facility as the operator workstation  102 , or in a different facility, such as a different healthcare institution or clinic. 
         [0030]    The networked workstation  142 , whether within the same facility or in a different facility as the operator workstation  102 , may gain remote access to the data processing server  114  or data store server  116  via the communication system  117 . Accordingly, multiple networked workstations  142  may have access to the data processing server  114  and the data store server  116 . In this manner, magnetic resonance data, reconstructed images, or other data may exchanged between the data processing server  114  or the data store server  116  and the networked workstations  142 , such that the data or images may be remotely processed by a networked workstation  142 . This data may be exchanged in any suitable format, such as in accordance with the transmission control protocol (TCP), the internet protocol (IP), or other known or suitable protocols. 
         [0031]    With reference to  FIG. 2 , the RF system  120  of  FIG. 1  will be further described. The RF system  120  includes a transmission channel  202  that produces a prescribed RF excitation field. The base, or carrier, frequency of this RF excitation field is produced under control of a frequency synthesizer  210  that receives a set of digital signals from the pulse sequence server  110 . These digital signals indicate the frequency and phase of the RF carrier signal produced at an output  212 . The RF carrier is applied to a modulator and up converter  214  where its amplitude is modulated in response to a signal, R(t), also received from the pulse sequence server  110 . The signal, R (t), defines the envelope of the RF excitation pulse to be produced and is produced by sequentially reading out a series of stored digital values. These stored digital values may be changed to enable any desired RF pulse envelope to be produced. 
         [0032]    The magnitude of the RF excitation pulse produced at output  216  is attenuated by an exciter attenuator circuit  218  that receives a digital command from the pulse sequence server  110 . The attenuated RF excitation pulses are then applied to a power amplifier  220  that drives the RF transmission coil  204 . 
         [0033]    The MR signal produced by the subject is picked up by the RF receiver coil  208  and applied through a preamplifier  222  to the input of a receiver attenuator  224 . The receiver attenuator  224  further amplifies the signal by an amount determined by a digital attenuation signal received from the pulse sequence server  110 . The received signal is at or around the Larmor frequency, and this high frequency signal is down converted in a two step process by a down converter  226 . The down converter  226  first mixes the MR signal with the carrier signal on line  212  and then mixes the resulting difference signal with a reference signal on line  228  that is produced by a reference frequency generator  230 . The down converted MR signal is applied to the input of an analog-to-digital (“ND”) converter  232  that samples and digitizes the analog signal. The sampled and digitized signal is then applied to a digital detector and signal processor  234  that produces 16-bit in-phase (I) values and 16-bit quadrature (Q) values corresponding to the received signal. The resulting stream of digitized I and Q values of the received signal are output to the data acquisition server  112 . In addition to generating the reference signal on line  228 , the reference frequency generator  230  also generates a sampling signal on line  236  that is applied to the A/D converter  232 . 
         [0034]    The basic MR systems and principles described above may be used to inform the design of other MR systems that share similar components but operate at very-different parameters. In one example, a low-field magnetic resonance imaging (IfMRI) system utilizes much of the above-described hardware, but has substantially reduced hardware requirements and a smaller hardware footprint. For example, referring to  FIG. 3 , a system  300  is illustrated that, instead of a 1.5 T or greater static magnetic field, utilizes a substantially smaller magnetic field. That is, in  FIG. 3 , as a non-limiting example, a 6.5 mT electromagnet-based scanner is illustrated. In particular, the system  300  includes a biplanar 6.5 mT electromagnet (B0)  302  that, for example, may be formed by inner B0 coils  304  and outer B0 coils  306 . Biplanar gradients  308  may extend across the B0 electromagnet  302 . 
         [0035]    The system  300  may be tailored for  1 H imaging by achieving a high B0 stability, high gradient slew rates, and low overall noise. To achieve these ends, a power supply, for example, with +/−1 ppm stability over 20 min and +/−2 ppm stability over 8 h, may be used and high current shielded cables may be deployed throughout the system  300 . In one non-limiting example, a power supply was adapted from a System 854T, produced by Danfysik, Taastrup, Denmark. The system  300  can operate inside a double-screened enclosure (ETS-Lindgren, St. Louis, Mo.) with a RF noise attenuation factor of 100 dB from 100 kHz to 1 GHz. In this example, the system may have a height, H, that is, as a non-limiting example, 220 cm. A cooling systems  310 , such as may include air-cooling ducts, may be included. 
         [0036]    Using the above-described system, TEMPOL (4-hydroxy-TEMPO) may be detected with very-high sensitivity by performing an OMRI process. TEMPOL, as used herein, refers to 4-Hydroxy-TEMPO 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. It is a heterocyclic compound. The present disclosure recognizes that, in a normal physiological state, TEMPOL does not cross the BBB. However, the present disclosure further recognizes that, because of its small size (172 Da), however, TEMPOL can cross the BBB under pathological circumstances associated with early BBB opening (e.g. ischemia), and act as an OMRI-detectable tracer. The use of TEMPOL as a small, exogenous OMRI agent allows monitoring BBB disruption in stroke at the hyperacute stage, much earlier than the traditional relaxation-based MRI contrast agents that rely on the leakage of larger molecules (such as Gd-DTPA) across the BBB. 
         [0037]    A 3D OMRI process can be performed using a variation of a balanced steady state free precession (b-SSFP) pulse sequence, for example, such as described in Sarracanie M et al. MRM 2013 DOI: 10.1002/mrm.24705. To achieve sensitivity of b-SSFP-based OMRI to free radical concentration, an NMR/ESR coil setup can be used. For one in vivo experiment, a single loop ESR coil  400  was arranged inside a solenoid NMR coil  402 , as illustrate din  FIG. 4 . Under anesthesia, MCAO occlusion was performed in a 3 month old Wistar rat by insertion of filament via external carotid artery. Following 75 min MCAO and 60 min reperfusion, 3.6 μl/gbw of 300 μM TEMPOL was injected into the carotid artery after which the animal was sacrificed and OMRI imaging begun. 
         [0038]    The sensitivity of b-SSFP-based OMRI to free radical concentration is shown in  FIG. 5 . The OMRI images demonstrate marked image-based free radical sensitivity. The OMRI enhancement image may be computed from a ratio of OMRI to MRI magnitude. In vivo OMRI signal enhancement in the frontal lobe and eye ipsilateral to the ischemic site is clearly visible in the OMRI images following reperfusion, as shown in  FIG. 6 . The phase of the OMRI image in  FIG. 6  provides sensitive contrast even in cases where the radical concentration is very low and the Overhauser enhancement may be small. 
         [0039]    Imaging has been performed using TEMPOL at low concentrations with OMRI methods in vitro, and crossing the BBB following ischemia/reperfusion in vivo. Thus, in accordance with the present disclosure, OMRI may be used in conjunction with stable free radical TEMPOL as an exogenously administered probe in hyperacute stroke. Also, in accordance with the present disclosure, TEMPOL may be used as a probe for observing early BBB breakdown following reperfusion. Additionally, as TEMPOL reduction has been used as a functional probe to study redox status in tissue, temporally resolved OMRI may be used to indicate the redox status of ischemic tissue. 
         [0040]    Thus, a system and method is described for Overhauser-enhanced MRI (OMRI) that can be used in combination with an exogenously administered free radical probe to, for example, tomographically probe blood brain barrier breakdown and tissue oxidative stress status in vivo. Use of a small molecular size free radical probe molecule, for example, allows detection of hyper-acute and mild BBB disruption. Time-dependent tomographic measurements of free radical concentration reveal the extent of local redox status as a new functional probe. Exogeneously administered free radical probe molecule may be specifically functionalized to serve as molecular imaging target, binding to fibrin, for instance. 
         [0041]    As opposed to relaxation-based MRI contrast mechanisms, free-radical OMRI signal enhancement can be modulated as desired by pulse sequence control of the ESR/electron paramagnetic resonance (EPR) drive field, enabling detection down to very-low radical concentrations to be made using a lock-in technique even in cases where the enhancement is small. The present disclosure advantageously provides a non-invasive, fast operation and reduced SAR at low magnetic field with b-SSFP OMRI sequences. 
         [0042]    Free radical imaging, by providing a tomographic measurement of oxidative stress, has the potential to transform both the research and clinical management of stroke. A better understanding of stroke physiopathology and stroke models can be achieved by studying BBB disruption in animals in vivo. The present disclosure offers a new tool for drug design and neuroprotection studies. 
         [0043]    Future clinical application of OMRI include acute stroke management (e.g., as a decision-making and prognostic tool), clinical research (including a more fundamental understanding of hemorrhagic transformation), and as a monitor of drug design and effectiveness. The ability to image and monitor very-early BBB disruption upon I/R, may also predict and prevent hemorrhagic transformation and complications of stroke treatments such as thrombolysis. 
         [0044]    The use of OMRI to image free radicals in vivo is an advantageous tool applicable to other neurologic diseases in which oxidative stress appears to play a significant role such as head trauma, Alzheimer&#39;s dementia and multiple sclerosis, and even in other organ systems. In cancer, measurement of tumor redox state in response to therapy may aid development of chemoprevention strategies, as well as monitor the impact of therapies directed to alleviate free radical-mediated cell damage. 
         [0045]    The present invention has been described in terms of one or more embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention.