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Development of a biomagnetism measurement system for small animals
International Congress Series 1300 (2007) 586 – 590
www.ics-elsevier.com
Development of a biomagnetism measurement system for small animals Masakazu Miyamoto a,⁎, Jun Kawai a , Miki Kawabata a , Tatsuyuki Shimozu a , Yoshiaki Adachi a , Gen Uehara a , Kazuo Komamura b , Naohiro Tsuyuguchi c , Yasuhiro Haruta d , Hisano Ogata a b
a Applied Electronics Laboratory, Kanazawa Institute of Technology, Japan Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Dynamics, Japan c Department of Neurosurgery, Osaka City University Medical School, Japan d MEG Center, Yokogawa Electric Co., Japan
Abstract. Accurate measurement of the biomagnetic signals from a rat or a mouse crucially benefits the development of new medicines and pathologies. In previous studies, MEG/MCG systems developed for humans were used to obtain small animal biomagnetic signals, but we only partially succeeded. The accuracy and efficiency of the results were insufficient because the systems were not designed to measure small animal MEG or MCG. In order to improve the efficiency and accuracy of small animal measurements, we have developed a biomagnetism measurement system suitable for small animals. The newly developed integrated 9ch Low-Tc SQUIDs magnetometer array is designed to improve spatial resolution. It has a 2.5 mm diameter pickup coil on each sensor and covers 8 mm × 8 mm measurement area. A single measurement by the sensor provides sufficient data for the analysis of small animal biosignals. Measurement efficiency and replicability has also been improved compared to conventional systems by the addition of a removable table and the 3-axis linear stage. The removable nonmagnetic table is attached to a 3-axis linear stage and its temperature is controlled by circulating hot water in order to keep subject stable while recording. The principal components of this system are integrated into a small transportable chassis. The dimension of the whole system is 1.4 m in width, 0.7 m in depth, 1.8 m in height. The small sized biomagnetism measurement system is easy to place in a typical lab space. © 2007 Elsevier B.V. All rights reserved. Keywords: Small animal; MEG; MCG; SQUID
⁎ Corresponding author. Tel.: +81 3 5545 8181; fax: +81 3 5545 8182. E-mail address: [email protected] (M. Miyamoto). 0531-5131/ © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2007.01.036
M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
587
1. Introduction In the area of medicine development, The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals of Human Use demands safety tests for newly approved drugs with respect to their proarrhythmic potential. The enactment of these guidelines by regulatory organizations will lead pharmaceutical companies to employ extra safety test process with small animals in its development process. However, obtaining biosignals, such as electrocardiograms, from a small animal is an inefficient process because many treatments are necessary for the object. The measured data are affected by electrode placement errors and changing electrode–skin contacts, which results in the impossibility of replicating the study and in reduced productivity. A biomagnetism measurement system, as a contact-free measurement method, has sufficient capability to improve measurement efficiency and it can provide an alternative method in terms of measurement replicability [1–3]. To improve on the conventional biosignal measurement systems, we have succeeded developing a small-sized biomagnetism measurement system for small animals. In this paper, we outline the system and show results for MCG signal measurements of a mouse using this system. 2. Instrument description 2.1. Magnetically shielded box and cryostat Fig. 1 shows the appearance of the measurement system. In the right side of the system, the magnetically shielded box is integrated with the cryostat. The cryostat, sensors and wiring for the sensors are shielded by Al plate (t = 3 mm) and two-layered mu-metal plate (t = 2 mm) from electromagnetic fields and magnetic fields that affect the performance of the sensors. The inside dimension of the shielded box is 500 mm in width, 300 mm in depth, 400 m in height.
Fig. 1. Overall view of the system.
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M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
For the administration of medicine, plastic tubes can be placed through small holes on its double-hinged door. This type door has proven to be easier to open and close with fewer parts, which improves the operation of the box. The shielding factor of the magnetically shielded box is more than 60 dB at 10 Hz. The cryostat has approximately 6 L capacity of liquid Helium and is placed on the top of the magnetically shielded box. It provides approximately 48 h of continuous biomagnetism measurement capability. 2.2. SQUID sensors The SQUID sensors are housed in a fiberglass reinforced plastic tube. The tube is 35 mm in diameter, and is placed at the center of the cryostat with its lid. The 9ch integrated SQUID sensor is attached at edge of the tube to minimize the gap between the subject and the pickup coil. The distance between the pickup coil and subject is 2 mm. The integrated sensor has nine of 2.5 mm diameter pickup coils, and which are arranged 3 × 3 square matrix with 2.75 mm distance between each coil [4]. The sensor covers an area of 8 mm × 8 mm which is adequate for MEG/MCG measurements of small animals. We have confirmed the noise of a sensor is less than 10 fT/rtHz. Figs. 2 and 3 show the appearance of the sensor and its noise characteristic, respectively. 2.3. Stage for subject The detachable plate for fixing a subject is placed on the 3-axis nonmagnetic linear stage. The 3-axis stage accurately controls the distance between sensor and the subject and the position of the observation area on the subject and improves productivity and effectiveness of measurement. During a measurement, the subject's temperature is stabilized by controlling the temperature of the plate with hot water which flows inside the plate. This capability also ensures the replicability of the measurements. The detachable plate saves effort of replacement for the subject by minimizing the preparatory operation in the narrow magnetic shielded box.
Fig. 2. Integrated 9ch SQUID sensor.
M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
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Fig. 3. Noise characteristic of the sensor.
2.4. Peripherals All components essential to the system are integrated into a small transportable chassis. The chassis also houses the peripherals: rotary vacuum pump, vacuum meter, liquid Helium level meter, source for the light inside the box. These are integrated into the chassis to improve maintainability of the system. The dimension of the chassis is 1.4 m in width, 0.7 m in depth, 1.8 m in height, and 300 kg in weight. Since its foot-print is about the same size of typical office desk, the system can be installed in a typical laboratory space with minimal work. 3. Measurement We measured a magnetocardiograph of a mouse using our biomagnetism measurement system. Figs. 4 and 5 show the waveform of the biomagnetism signals from a mouse. The trace on the Fig. 4 shows raw data of the measurement. The trace on the Fig. 5 is 20 times of averaged data and shows a clear QRS complex which amplitude is approximately 40pTp-p.
Fig. 4. Measurement example: MCG of a mouse [no average].
Fig. 5. Measurement example: MCG of a mouse [20 beats averaged].
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M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
4. Discussion We developed a biomagnetism measurement system that measures small animal biomagnetic signals. The system incorporates a newly developed low noise integrated 9ch Low-Tc SQUIDs magnetometer array. A small chassis contains all the essential components. The feasibility of small animal MCG measurement using the system was established. In the future, we will improve the system by downsizing and developing new software which will improve the efficiency and usability of this system for the measurement of biomagnetic signals of small animals. References [1] U. Steinhoff, et al., MCG as a tool for drug safety testing and knock-out model animal studies, BIOMAG (2004) P2-5 375. [2] Y. Ono, et al., Development of biomagnetic measurement system for mice with high spatial resolution, Applied Physics Letters 85 (2) (July 2004) 332. [3] J. Kawai, et al., Mouse and rat MCG system using a single-chip SQUID magnetometer array, The Journal of Japan Biomagnetism and Bioelectromagnetics Society 18 (1) (July 2005) O2-1. [4] J. Kawai, et al., Fabrication and characterization of an integrated 9-channel superconducting quantum interference device magnetometer, IEEE Transactions on Applied Superconductivity 15 (2) (June 2005) 821.
www.ics-elsevier.com
Development of a biomagnetism measurement system for small animals Masakazu Miyamoto a,⁎, Jun Kawai a , Miki Kawabata a , Tatsuyuki Shimozu a , Yoshiaki Adachi a , Gen Uehara a , Kazuo Komamura b , Naohiro Tsuyuguchi c , Yasuhiro Haruta d , Hisano Ogata a b
a Applied Electronics Laboratory, Kanazawa Institute of Technology, Japan Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Dynamics, Japan c Department of Neurosurgery, Osaka City University Medical School, Japan d MEG Center, Yokogawa Electric Co., Japan
Abstract. Accurate measurement of the biomagnetic signals from a rat or a mouse crucially benefits the development of new medicines and pathologies. In previous studies, MEG/MCG systems developed for humans were used to obtain small animal biomagnetic signals, but we only partially succeeded. The accuracy and efficiency of the results were insufficient because the systems were not designed to measure small animal MEG or MCG. In order to improve the efficiency and accuracy of small animal measurements, we have developed a biomagnetism measurement system suitable for small animals. The newly developed integrated 9ch Low-Tc SQUIDs magnetometer array is designed to improve spatial resolution. It has a 2.5 mm diameter pickup coil on each sensor and covers 8 mm × 8 mm measurement area. A single measurement by the sensor provides sufficient data for the analysis of small animal biosignals. Measurement efficiency and replicability has also been improved compared to conventional systems by the addition of a removable table and the 3-axis linear stage. The removable nonmagnetic table is attached to a 3-axis linear stage and its temperature is controlled by circulating hot water in order to keep subject stable while recording. The principal components of this system are integrated into a small transportable chassis. The dimension of the whole system is 1.4 m in width, 0.7 m in depth, 1.8 m in height. The small sized biomagnetism measurement system is easy to place in a typical lab space. © 2007 Elsevier B.V. All rights reserved. Keywords: Small animal; MEG; MCG; SQUID
⁎ Corresponding author. Tel.: +81 3 5545 8181; fax: +81 3 5545 8182. E-mail address: [email protected] (M. Miyamoto). 0531-5131/ © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2007.01.036
M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
587
1. Introduction In the area of medicine development, The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals of Human Use demands safety tests for newly approved drugs with respect to their proarrhythmic potential. The enactment of these guidelines by regulatory organizations will lead pharmaceutical companies to employ extra safety test process with small animals in its development process. However, obtaining biosignals, such as electrocardiograms, from a small animal is an inefficient process because many treatments are necessary for the object. The measured data are affected by electrode placement errors and changing electrode–skin contacts, which results in the impossibility of replicating the study and in reduced productivity. A biomagnetism measurement system, as a contact-free measurement method, has sufficient capability to improve measurement efficiency and it can provide an alternative method in terms of measurement replicability [1–3]. To improve on the conventional biosignal measurement systems, we have succeeded developing a small-sized biomagnetism measurement system for small animals. In this paper, we outline the system and show results for MCG signal measurements of a mouse using this system. 2. Instrument description 2.1. Magnetically shielded box and cryostat Fig. 1 shows the appearance of the measurement system. In the right side of the system, the magnetically shielded box is integrated with the cryostat. The cryostat, sensors and wiring for the sensors are shielded by Al plate (t = 3 mm) and two-layered mu-metal plate (t = 2 mm) from electromagnetic fields and magnetic fields that affect the performance of the sensors. The inside dimension of the shielded box is 500 mm in width, 300 mm in depth, 400 m in height.
Fig. 1. Overall view of the system.
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M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
For the administration of medicine, plastic tubes can be placed through small holes on its double-hinged door. This type door has proven to be easier to open and close with fewer parts, which improves the operation of the box. The shielding factor of the magnetically shielded box is more than 60 dB at 10 Hz. The cryostat has approximately 6 L capacity of liquid Helium and is placed on the top of the magnetically shielded box. It provides approximately 48 h of continuous biomagnetism measurement capability. 2.2. SQUID sensors The SQUID sensors are housed in a fiberglass reinforced plastic tube. The tube is 35 mm in diameter, and is placed at the center of the cryostat with its lid. The 9ch integrated SQUID sensor is attached at edge of the tube to minimize the gap between the subject and the pickup coil. The distance between the pickup coil and subject is 2 mm. The integrated sensor has nine of 2.5 mm diameter pickup coils, and which are arranged 3 × 3 square matrix with 2.75 mm distance between each coil [4]. The sensor covers an area of 8 mm × 8 mm which is adequate for MEG/MCG measurements of small animals. We have confirmed the noise of a sensor is less than 10 fT/rtHz. Figs. 2 and 3 show the appearance of the sensor and its noise characteristic, respectively. 2.3. Stage for subject The detachable plate for fixing a subject is placed on the 3-axis nonmagnetic linear stage. The 3-axis stage accurately controls the distance between sensor and the subject and the position of the observation area on the subject and improves productivity and effectiveness of measurement. During a measurement, the subject's temperature is stabilized by controlling the temperature of the plate with hot water which flows inside the plate. This capability also ensures the replicability of the measurements. The detachable plate saves effort of replacement for the subject by minimizing the preparatory operation in the narrow magnetic shielded box.
Fig. 2. Integrated 9ch SQUID sensor.
M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
589
Fig. 3. Noise characteristic of the sensor.
2.4. Peripherals All components essential to the system are integrated into a small transportable chassis. The chassis also houses the peripherals: rotary vacuum pump, vacuum meter, liquid Helium level meter, source for the light inside the box. These are integrated into the chassis to improve maintainability of the system. The dimension of the chassis is 1.4 m in width, 0.7 m in depth, 1.8 m in height, and 300 kg in weight. Since its foot-print is about the same size of typical office desk, the system can be installed in a typical laboratory space with minimal work. 3. Measurement We measured a magnetocardiograph of a mouse using our biomagnetism measurement system. Figs. 4 and 5 show the waveform of the biomagnetism signals from a mouse. The trace on the Fig. 4 shows raw data of the measurement. The trace on the Fig. 5 is 20 times of averaged data and shows a clear QRS complex which amplitude is approximately 40pTp-p.
Fig. 4. Measurement example: MCG of a mouse [no average].
Fig. 5. Measurement example: MCG of a mouse [20 beats averaged].
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M. Miyamoto et al. / International Congress Series 1300 (2007) 586–590
4. Discussion We developed a biomagnetism measurement system that measures small animal biomagnetic signals. The system incorporates a newly developed low noise integrated 9ch Low-Tc SQUIDs magnetometer array. A small chassis contains all the essential components. The feasibility of small animal MCG measurement using the system was established. In the future, we will improve the system by downsizing and developing new software which will improve the efficiency and usability of this system for the measurement of biomagnetic signals of small animals. References [1] U. Steinhoff, et al., MCG as a tool for drug safety testing and knock-out model animal studies, BIOMAG (2004) P2-5 375. [2] Y. Ono, et al., Development of biomagnetic measurement system for mice with high spatial resolution, Applied Physics Letters 85 (2) (July 2004) 332. [3] J. Kawai, et al., Mouse and rat MCG system using a single-chip SQUID magnetometer array, The Journal of Japan Biomagnetism and Bioelectromagnetics Society 18 (1) (July 2005) O2-1. [4] J. Kawai, et al., Fabrication and characterization of an integrated 9-channel superconducting quantum interference device magnetometer, IEEE Transactions on Applied Superconductivity 15 (2) (June 2005) 821.