WO2008091712A2

WO2008091712A2 - Low field electron paramagnetic resonance imaging with squid detection

Info

Publication number: WO2008091712A2
Application number: PCT/US2008/001136
Authority: WO
Inventors: Inseob Hanh; Peter Day; Konstantin I. Penanen; Byeong H. Eom; Mark S. Cohen
Original assignee: California Institute Of Technology
Priority date: 2007-01-25
Filing date: 2008-01-28
Publication date: 2008-07-31
Also published as: WO2008091712A3

Abstract

A flux transformer is magnetically coupled to a SQUID (112), and a plurality of SQUIDs (114B1 115B, 116B, 117B), connected in series, is magnetically coupled to the output of the SQUID. Alternatively, a flux transformer (108, 110) and a modulating coil (330) are magnetically coupled to a SQUID and an oscillator drives the modulating coil (230) at a frequency f. A processing system (306) mixes the output signal of the SQUID with sin(wt) and cos(2wt), where w = 2TT.f.

Description

LOW FIELD ELECTRON PARAMAGNETIC RESONANCE IMAGING WITH

SQUID DETECTION

Priority Claim

[0001] This application claims the benefit of U.S. Provisional Application No.

60/897,356, filed 25 January 2007.

Government Interest

[0002] The invention claimed herein was made in the performance of work under a NASA contract, and is subject to the provisions of Public Law 96-517 (35 USC 202) in which the Contractor has elected to retain title.

Field [0003] The present invention relates to electron paramagnetic resonance imaging.

Background

[0004] Electron paramagnetic resonance (EPR) imaging has been recently recognized as an important tool for non-invasive imaging of free radicals and REDOX (reduction/oxidization) metabolism. In principle, electron paramagnetic resonance may be observed at frequencies of a few MHz in magnetic fields of a few Gauss, up to the microwave region in a magnetic field of a few thousand Gauss. Traditionally, the latter frequency region is often chosen because the signal-to-noise ratio is usually much improved with the use of relatively high magnetic fields, which implies a relatively high Lamour frequency. However, the use of microwave radiation (e.g., in the 1 GHz to 60 GHz region) is currently known to require a special resonance cavity that is not suitable for non-invasive imaging of a large size living animal, such as a human. For example, the motion of an animal in a resonance cavity, such as motion due to respiration or a beating heart, may cause changes in the resonance frequency of the cavity. In addition, generally the skin depth decreases as the frequency of the electromagnetic radiation increases, which may preclude imaging within regions of interest in a human for EPR imaging systems operating in the 1 GHz to 60 GHz region. Furthermore, high magnetic fields often pose a safety hazard. [0005] The high frequency microwave radiation of prior art EPR imaging systems

attorney docket cit.4821PCT client docket CIT-4821 appears to pose a physical and biological hindrance to the advance of EPR imaging technology for large size living animals. Recently, there has been work in developing an EPR imaging system that employs low magnetic fields (e.g., on the order of 10 mT) at radio frequencies (e.g., about 300 MHz) where the RF (radio frequency) energy may penetrate into biological objects. However, EPR techniques developed for clinical applications to date still rely on conventional RF detection schemes which are believed to degrade signal-to-noise ratio at low magnetic fields.

Brief Description of the Drawings

[0006] Fig. 1 illustrates an EPR SQUID detection system according to an embodiment.

[0007] Fig. 2 illustrates a coil system according to the embodiment of Fig. 1.

[0008] Fig. 3 illustrates a microwave EPR SQUID detection system according to an embodiment.

Description of Embodiments

[0009] In the description that follows, the scope of the term "some embodiments" is not to be so limited as to mean more than one embodiment, but rather, the scope may include one embodiment, more than one embodiment, or perhaps all embodiments. [0010] Fig. 1 is a schematic illustrating EPR detection with a SQUID

(Superconducting Quantum Interference Device) according to an embodiment. Object 102 is the specimen (e.g., human) to be imaged. Coil systemlO4 comprises various coils to apply to object 102 a magnetic field having a spatial gradient, and to provide pulses of electromagnetic excitation to object 102 so that electron spin echo pulses may be detected. As is well known, the Lamour frequency of an electron spin echo pulse depends on magnetic field strength, so that spectral analysis applied to the received electron spin echo pulses yields imaging information. For ease of illustration, the various components making up coil system 104 are not shown in Fig. 1 , but are described later with respect to Fig. 2.

[0011] The remaining components in the detector of Fig. 1 are kept at a low temperature during operation so that they operate in their superconducting state. For some embodiments, the temperature is about 4.2 Kelvin, although for some embodiments, high-temperature superconductors may be used. The superconducting

attorney docket cit.4821 PCT client docket CIT-4821 temperature is maintained by operating these components in a Dewar or cryostat, with electrical connections available for room temperature components. For ease of illustration, only a portion of a Dewar, labeled as 106, is shown in Fig. 1. [0012] The EPR imaging embodiment of Fig. 1 comprises a second order gradiometer within dashed rectangle 108 to receive the electron spin echo pulses from object 102. In the particular embodiment of Fig. 1, the gradiometer comprises two turns (108A), four turns (108B), and two turns (108C) of 80 μm diameter Nb (Niobium) wire wound on a MACOR® former grooved for the wire. MACOR is a registered trademark of Corning Glass Works Corporation, Houghton Park, Corning, New York. For the particular embodiment of Fig. 1, the gradiometer baseline is 55 mm and the loop diameter is 25.4 mm. The inductance of the gradiometer is 1.02 μH. The total effective sensing area of the gradiometer is about 6.5 mm². The average distance from the gradiometer to object 102 is about 15 mm. By using a gradiometer, the EPR imaging system of Fig. 1 is not sensitive to homogeneous magnetic fields, such as unwanted magnetic fields from far away sources that are essentially homogenous over the scale of the gradiometer. Other embodiments other than that described with reference to Fig. 1 may utilize other types of pickup coils sensitive to electron spin echo pulses.

[0013] Coil 110 is electrically connected to the gradiometer and is magnetically coupled to SQUID 1 12. SQUID 112 comprises SQUID loop 112A and Joshepson junctions 1 12B, and for the embodiment of Fig. 1 is a DC (Direct Current) SQUID. Magnetic flux from coil 110 links SQUID loop 112A. The combination of coil 110 and the gradiometer serves as a flux transformer. In practice, the physical dimension of SQUID 1 12 is on the order of microns, whereas the gradiometer is on the order of centimeters.

[0014] Using a flux transformer is a practical way of providing SQUID detection of magnetic flux due to the electron spin echo pulses generated by the unpaired electrons within object 102. Furthermore, by using SQUID 1 12 with the flux transformer, the operation frequency may be significantly lowered when compared to prior art systems. For example, for some embodiments, the operating frequency may be 1.4 MHz at the Earth's magnetic field of 0.5 Gauss. At this relatively low frequency, the electron spin echo pulses may be detected by use of a gradiometer without the need for a cavity

attorney docket cit.4821PCT client docket CIT-4821 resonator. Furthermore, the skin depth of muscle tissues at 2 MHz is approximately 30 cm. The Specific Absorption Rate (SAR) is essentially negligible for an operating frequency in the 1 MHz range.

[0015] The embodiment of Fig. 1 also makes use of a SQUID array amplifier, comprising a plurality of coils coupled to the output of SQUID 1 12, and a plurality of

SQUIDs magnetically coupled to the coils. For simplicity, only four SQUIDs in an array amplifier are shown in Fig. 1, but in practice, there may be on the order of one hundred

SQUIDs in a SQUID array amplifier. In the simplified SQUID array amplifier of Fig. 1, coils 114A, 1 15 A, 116A, and 117A are connected in series with each other, and connected to the output of SQUID ,112 by way of resistor 1 18. SQUIDs 114B, 115B,

116B, and 117B are connected in series with each other, where SQUID 114B is magnetically coupled to coil 114A, SQUID 115B is magnetically coupled to coil 115A,

SQUID 116B is magnetically coupled to coil 1 16A, and SQUID 1 17B is magnetically coupled to coil 1 17A.

[0016] The output of the SQUID array amplifier is taken across series-connected

SQUIDs 114B, 115B, 116B, and 117B. For some embodiments, the SQUID array amplifier is expected to have a bandwidth of about 1 MHz using commercially available

SQUIDs.

[0017] Well-known components used in the art of SQUID detectors are not shown in Fig. 1 for simplicity. For example, typically, SQUID readout electronics employ feedback to keep the flux in the SQUID loop at a sensitive part of its response

(modulation) function and to linearize the response.

[0018] Fig. 2 is a schematic illustration of a coil system for generating magnetic fields so that unpaired electrons in object 102 give off electron spin echo pulses. Fig. 2 illustrates a coil system comprising square Helmholtz coil 202 to provide a homogenous static magnetic field, square Maxwell coil 204 to provide a z-gradient in the applied magnetic field, x-gradient coil 206 to provide an x-gradient in the applied magnetic field, and y-gradient coil 208 to provide a y-gradient in the applied magnetic field. The x-y-z directions are indicated by the coordinate system displayed in Fig. 2.

[0019] Fig. 2 further illustrates pre-polarizing coil 210 to increase the magnetization of object 102, and excitation coil 212 to provide an oscillating magnetic

attorney docket cit.4821 PCT client docket CIT-4821 field perpendicular to the homogenous static magnetic field. The excitation pulses generated by excitation coil 212 provide the π/2 and π magnetic pulses that are often described semi-classically as tipping the magnetization vectors in object 102 so that electron spin echo pulses are generated.

[0020] Fig. 2 also illustrates a portion of a Dewar (106) to contain the flux transformer and the SQUID detector components illustrated in Fig. 1. Fig. 2, like Fig. 1, is a schematic, so that relative sizes are not implied. Furthermore, the coils illustrated in Fig. 2 are simplified, so that electrical connections and individual turns are not shown, but rather, the coils are schematically illustrated as simple rectangles, or simple cylinders (to represent solenoids, to be discussed later) in the case of pre-polarization coil 210. [0021] The measurement sequence includes a pre-polarization interval, followed by encoding and acquisition. Pre-polarization coil 210 polarizes object 102 in a higher magnetic field than the homogeneous static magnetic field provided by Helmholtz coil 202, and this pre-polarization technique uses a fast ramping-down of the pre-polarizing field. For the embodiment of Fig. 2, pre-polarizing coil 210 comprises two identical short and thick solenoids, and has a symmetric design so that it does not induce an appreciable magnetic flux to the gradiometer. In this way, a current-limiting device is not necessarily needed in the gradiometer to protect SQUID 1 12 from an excessive current that may be induced by a fast change (about 10 T/s) of the pre-polarizing field. It was found that any remaining residual asymmetry in the coil design and position of pre-polarization coil 210 may be sufficiently corrected by moving Dewar 106 with respect to pre-polarization coil 210 while observing the SQUID voltage response to a low-frequency AC (Alternating Current) magnetic field induced in pre-polarization coil 210. For some embodiments, the polarization provided by pre-polarization coil 210 may not be required for the EPR detection if the signal strength is large enough.

[0022] The shape and the separation of the two solenoids for pre-polarization coil

210 may be chosen for easy construction, convenient imaging volume access, and based upon the tentative sample size of object 102. The thickness and the diameter of the wire for pre-polarization coil 210 were determined to maximize the field strength at the center at fixed power. Once the shape and the size are determined, the ratio of the field strength to the applied power is independent of the wire diameter and the number of windings.

attorney docket cit.4821 PCT client docket CIT-4821 The coil former was built out of fiberglass to prevent eddy current effects and induced magnetization. For this same reason, most of the experimental setup for an embodiment was built out of various fiberglass materials with adequate magnetic characteristics for each component.

[0023] For some embodiments, it was found that if the two solenoids forming pre-polarization coil 210 were aligned coaxially, then the close proximity of the massive copper coils to the gradiometer induced significant thermal noise. To reduce the noise and to increase the magnetic field with the distance from the gradiometer, the solenoids were aligned in a V shape so that the separation is larger at the top end near the gradiometer. This arrangement was found to partially compensate the sensitivity profile of the gradiometer.

[0024] For an experimental embodiment, the parameters for the coil system of

Fig. 2 may be described as follows. For pre-polarization coil 210, two solenoids were used, each with an outer diameter of 204 mm, an inner diameter of 38 mm, a thickness of 35 mm, with a top separation of 149 mm and a bottom separation of 19 mm. The windings comprised 398 turns in 6 parallel groups, to provide a magnetic field of 2.4 mT/A. Helmholtz coil 202 is a square shaped coil with a 1 108 mm side and a separation of 603 mm. The windings comprised 30 turns to provide 44 μT/A. Maxwell coil 204 is a square shaped coil with a 1 108 mm side, with windings comprising 15 turns in two parallel groups, to provide a magnetic field gradient of 32 μTm 'A^'1. X-gradient coil 206 and y-gradient coil 208 are each a bi-planar coil, each with a long side of 1087 mm, a short side of 188 mm, having a plane separation of 1 108 mm and an in-plane separation of 647 mm. Each has windings comprising 15 turns in two parallel groups, to provide a magnetic field gradient of 12 μTnV'A^"1. Excitation coil 212 comprised a pair of rectangular coils, each with a long side of 400 mm, a short side of 319 mm, with a separation of 183 mm, with each winding comprising 2 turns to provide a magnetic field of 9.5 μT/A.

[0025] Fig. 3 is a schematic illustrating a microwave SQUID detector system according to another embodiment. Again, only a portion of Dewar 106 is shown, where system components 302, 304, 306, 308, 310, and 312, are electronic systems that need not be cooled, or at least not cooled to the same low temperature as the rest of the system

attorney docket cit.4821 PCT client docket CIT-4821 components in the SQUID detector system.

[0026] Components 316 and 318 are co-planar waveguides with connections to frequency up-converter 302 and high electron mobility transistor (HEMT) amplifier 314. Their frequency of operation for some embodiments may be about 10 GHz. Co-planar waveguide 324 may comprise a meandering half-wavelength line (one-half the wavelength of the carrier provided by frequency up-converter 302). The combination of waveguide 324 and capacitors 320 and 322 form a resonator loaded by SQUID 326. SQUID 326 is a DC (Direct Current) SQUID that may be biased by a direct current, indicated by bias port 328. However, for some embodiments, bias port 328 is optional, and the bias may be provided by the microwave current by way of co-planar waveguides 316 and 318. In addition to coil 1 10, another coil, modulation coil 330, is magnetically coupled to SQUID 326 and is driven by oscillator 312 at some specified frequency. Dashed line 332 indicates that for some embodiments the components within dashed line 332 may be fabricated on a single chip.

[0027] The quality factor of the resonator provided by components 320, 322, and

324, varies as the flux state of SQUID 326 changes. Typically, readout electronics for a SQUID employ feedback to keep the flux in the SQUID at a sensitive part of its response function, and to linearize its output. However, the embodiment of Fig. 3 may operate SQUID 326 in a non-flux-locked mode. Based on prior art systems, it might be expected that operation in a non-flux-locked mode might be hampered by the periodic nature of the SQUID response function, which limits the dynamic range and may lead to the possibility that stray magnetic fields bias the SQUID at a point of degraded sensitivity. However, in the embodiment of Fig. 3, this problem is mitigated by applying a high frequency modulation to SQUID 326 by use of modulation coil 330, and by implementing what might be termed a / and 2/ modulation scheme, where / is the modulation frequency provided by oscillator 312.

[0028] The voltage signal provided by SQUID chip 332, after amplified by amplifier 314 and down-converted by frequency down-converter 310, is digitized by analog-to-digital converter 308 and demodulated by processing system 306 to implement the / and 2/ modulation scheme. In this scheme, the output of SQUID chip 332 is lock- in detected both at the frequencies / and 2/ to provide output signals

attorney docket cit.4821 PCT cl ient docket CIT-4821 χ(φ) = (sin ωt ■ 5(Φ + A sin ωt)>, and y(Φ) = (cos 2ωt ^■ 5(Φ + A sin ωt)), where ω = 2π/ is the angular frequency in radians of the flux modulation provided by modulation coil 330, A is the amplitude of this flux modulation, 5 is the SQUID response (modulation) function, Φ is the magnetic flux linking SQUID 326 due to coil 110, and ( ) denotes a time average.

[0029] Because the frequency ω = 2π/ is generated locally, standard phase locked loop technology may be utilized to generate the sinusoids sin ωt and cos 2ωt. The time average ( > may be performed in the analog domain by a mixer followed by a low pass filter. These techniques are well known in the art of communication technology. [0030] A phase angle may be defined by

«^♦) = ^«*^» - where X and Y are the maximum values of X(Φ) and V(Φ), respectively. It can be shown that the response Θ(Φ) is close to being linear in its argument Φ for useful values of flux Φ. It was found that there may be a periodic residual non-linearity, but it is expected that the residual non-linearity may be corrected by post-processing in practical applications. [0031] For some embodiments, the modulation frequency / may be about 100

MHz, the carrier frequency provided by frequency up-converter 302 may be about 10 GHz, and the bandwidth of the system may be about 10 MHz. In an experimental embodiment, the microwave signal provided over waveguide 318 was amplified with a 4 to 12 GHz HEMT amplifier with a noise temperature of 5K, and a mixer was used to demodulate the microwave signal to recover the 10 MHz SQUID signal. A second demodulator mixed this signal down to baseband. For some embodiments, the time average may be performed by low pass filtering the output of the mixer. [0032] Analog-to-digital conversion is applied, followed by digital signal processing to provide the phase angle Θ(Φ). Processing system 306 includes the digital signal processing, and includes other control functions for operating frequency up- converter 302 by way of digital-to-analog converter 304. Some or all of the control and processing represented by processing system 306 may be implemented by special

attorney docket cit.4821 PCT client docket CIT-4821 purpose hardware, firmware, software operating on a programmable processor system, or perhaps some combination thereof.

[0033] Multiple versions of the embodiment illustrated in Fig. 3 may be configured into an array of SQUID detectors that utilize frequency multiplexing to significantly reduce the number of electrical connections to the room temperature environment. For such embodiments, waveguides 316 and 318 may be shared by a plurality of resonators, each loaded by a SQUID with its own modulation coil and gradiometer. Each resonator is tuned to a different carrier frequency. A comb of microwave frequencies is used to simultaneously excite all of the resonators of the array. Standard frequency de-multiplexing techniques may be employed to separate out the SQUID responses, followed by the / and 2/ modulation scheme as described earlier. (The modulation frequency / should not be confused with the carrier frequencies.) To further reduce the number of warm connections, for some embodiments each SQUID may be biased by the microwave carrier amplitude, and the modulation coils may be connected in series. As a result, such embodiments may utilize thousands of detectors, where the warm signal connections comprise only two pairs of wires for the modulation coils, and a single microwave coaxial cable.

[0034] Various modifications may be made to the disclosed embodiments without departing from the scope of the invention as defined below.

[0035] Throughout the description of the embodiments, various mathematical relationships are used to describe relationships among one or more quantities. For example, a mathematical relationship or mathematical transformation may express a relationship by which a quantity is derived from one or more other quantities by way of various mathematical operations, such as addition, subtraction, multiplication, division, etc. Or, a mathematical relationship may indicate that a quantity is larger, smaller, or equal to another quantity. These relationships and transformations are in practice not satisfied exactly, and should therefore be interpreted as "designed for" relationships and transformations. One of ordinary skill in the art may design various working embodiments to satisfy various mathematical relationships or transformations, but these relationships or transformations can only be met within the tolerances of the technology available to the practitioner.

attorney docket cit.4821 PCT client docket CIT-4821 [0036] Accordingly, in the following claims, it is to be understood that claimed mathematical relationships or transformations can in practice only be met within the tolerances or precision of the technology available to the practitioner, and that the scope of the claimed subject matter includes those embodiments that substantially satisfy the mathematical relationships or transformations so claimed.

attorney docket cit.4821 PCT client docket CIT-4821

Claims

What is claimed is:

1. An apparatus comprising: a SQUID; a flux transformer magnetically coupled to the SQUID; and a plurality of SQUIDs connected in series to each other and magnetically coupled to the SQUID.

2. The apparatus as set forth in claim 1, the flux transformer comprising a gradiometer.

3. The apparatus as set forth in claim 1, further comprising a plurality of coils in one-to-one correspondence with the plurality of SQUIDs, each coil magnetically coupled to a corresponding SQUID, where the plurality of coils are connected in series with each other and coupled to the SQUID.

4. The apparatus as set forth in claim 3, the flux transformer comprising a gradiometer.

5. An apparatus comprising: a SQUID; a flux transformer magnetically coupled to the SQUID; and a modulating coil magnetically coupled to the SQUID.

6. The apparatus as set forth in claim 5, the SQUID providing an output signal, the apparatus further comprising: an oscillator to drive the modulating coil at a frequency /; and a processing system to mix the output signal of the SQUID with the sinusoids sin ωt and cos 2ωt, where ω = 2π/.

7. The apparatus as set forth in claim 6, the processing system to provide the signals

attorney docket cit.4821 PCT client docket CIT-4821 X and Y, where X = (sin ωt ^• S) and Y = (cos 2ωt • 5), where S denotes the output signal of the SQUID and ( ) denotes a time average.

8. The apparatus as set forth in claim 7, the processing system comprising a mixer and a low pass filter to provide the time averages X = (sin ωt • S) and Y = (cos 2ωt • S).

9. The apparatus as set forth in claim 7, the processing system to provide a phase angle Θ, where

^{Θ = arctan} (^)' where Y_m is a maximum of Y, and X_m is a maximum of X.

10. The apparatus as set forth in claim 5, the flux transformer comprising a gradiometer.

1 1. The apparatus as set forth in claim 5, further comprising: a resonator coupled to the SQUID.

12. An apparatus comprising: a plurality of circuits, each circuit comprising: a SQUID; a resonator coupled to the SQUID and having a unique resonant frequency; a flux transformer magnetically coupled to the SQUID; and a modulating coil magnetically coupled to the SQUID; and a processing system to simultaneously excite all the resonators.

13. The apparatus as set forth in claim 12, each circuit providing an output signal, the apparatus further comprising: an oscillator to drive the modulating coil for each circuit at a frequency /; the processing system to mix the output signal of each circuit with the sinusoids attorney docket cit.4821 PCT client docket CIT-4821 sin ωt and cos 2ωt, where ω = 2πf.

14. The apparatus as set forth in claim 13, the processing system to provide for each circuit a pair of signals X and Y, where X = (sin ωt • S) and Y = (cos 2ωt • S), where S denotes the output signal of the SQUID in the circuit, and ( ) denotes a time average.

15. The apparatus as set forth in claim 14, the processing system comprising a mixer and a low pass filter to provide the time averages X = (sin ωt • S) and Y = (cos 2ωt • S) for each circuit.

16. The apparatus as set forth in claim 14, the processing system to provide a phase angle Θ for each circuit, where

^{Θ = arctan} (^)' where for each circuit Y_7n is a maximum of Y, and X_m is a maximum of X.

attorney docket cit.4821 PCT client docket CIT-4821