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QUALITY OF IN VIVO ELECTRICAL MEASUREMENTS INSIDE AN MRI MAGNET Joanna Tuppurainen1,*, Jarno M. A. Tanskanen1,2, and Markku Penttonen1,† 1 Cognitive Neurobiology Laboratory, Department of Neurobiology 2 Department of Biomedical NMR A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, FINLAND * [email protected], [email protected], †[email protected] ABSTRACT In this study, we investigate the quality of in vivo electrical measurements, i.e., field potentials within a living brain and electrocardiogram, from a subject (rat) in the static magnetic field of a magnetic resonance imagining (MRI) equipment. Generally, such a magnetic field is known to introduce measurement errors. The presented evaluation is a prerequisite for all our later research involving simultaneous electrical measurements and functional MRI. The in-magnet measurements are adequate for event identification (e.g., heart beat registration), animal status monitoring, triggering of external stimulation and fMRI, and brain oscillation frequency analysis. 1. INTRODUCTION Neuronal network oscillations are characteristics of the nervous system. Both the neuronal cell membrane properties and synaptic connections contribute to the generation of oscillations at the single cell and network levels. In the awake state, oscillations contribute at least to sensory perception, movement, and learning. During sleep, oscillations may be important for keeping the brain in a state of readiness for an unexpected awakening and for converting during awake state acquired short-term memories to permanent ones [1]. Several forms of oscillations are present in the hippocampus [2]. Theta (4-8 Hz) and gamma oscillation (3070 Hz) (Figure 1) are present during active interaction with the environment and thus may be related to the acquisition of new information. During sleep, fast oscillations (100-200 Hz) occur irregularly as short bursts. They may be involved in the transfer of memories to the cerebral cortex. Also slow oscillation (0.4-1 Hz) and very slow (0.01-0.06 Hz) oscillation are prominent [3], but their behavioral significance is not known. Oscillations also contribute to abnormal states of brain activity. For example, slow sleep oscillations may gradually transform into epileptic seizures in the cortex [1]. Moreover, hippocampus shows severe pathology after epileptic seizures. In search for knowledge of the basic functioning of the brain, new brain diagnostic tools, and cures for certain brain disorders, such as epilepsy, several measurement and imagining methods are in everyday use [4,5,6]. Electrophysiological measurements have been used as a straightforward indicator of neuronal activation and inactivation in the brain. Electroencephalogram (EEG) is measured on intact skin of the rat’s head, and field potentials (FP) from extracellular space within the brain tissue. The anatomy of the hippocampus is simple [7], which makes it easier to perform FP measurements in the hippocampus than in the cerebral cortex. Neuronal activation maps acquired with functional magnetic resonance imaging (fMRI) represent regional changes in blood volume, blood flow, and oxygenation. Neuronal activity increases both blood flow and blood volume in close vicinity of the activated area, which causes measurable changes in the MRI signal. Blood-oxygenation-dependent (BOLD) fMRI [6,8] has been widely applied [5,6] for mapping of brain activity, research on basic brain functionality, and for the diagnostics of deficient brain functioning. Even tough it is likely that there is a tight coupling between neuronal activity and vascular responses [9], the relation of neural activation and BOLD response is not exactly known [10]. BOLD response is expected to be only a few percents. Changes of this magnitude, however, are known to be consistently detectable [11]. Functional imaging is commonly applied in diagnosis and treatment of epilepsy [12]. During fMRI, subject’s status can be observed via EEG measurements, which can be used to initiate MRI at the onset of an epileptic seizure. These measurements can further be combined with FP measurements directly from the living epileptic brain with a single or multichannel recording electrode inserted into the brain structure of interest. 0.4 0.6 0.5 0.4 −0.2 −0.4 −0.6 Voltage (mV) 0 0 Voltage (mV) Voltage (mV) 0.2 −0.5 −1 0.2 0 −0.2 −0.8 −1 0 2 4 6 Time (s) −1.5 0 2 4 6 Time (s) −0.4 0 0.2 0.4 0.6 0.8 1 Time (s) 1.2 1.4 1.6 1.8 2 Figure 1. Typical theta (3.5 Hz, left) and low frequency (0.7 Hz, middle) oscillations measured from the hippocampus of an anesthetized rat inside an MRI magnet. Gamma oscillations (37 Hz) modulated by a carrier oscillation of 2 Hz are shown on the right. Our goal is to study oscillations and epilepsy with simultaneous fMRI and FP measurements directly from a living brain of a rat. We aim to combine BOLD and FP measurements in order to better understand the relation between BOLD response and the underlying electrical activity. A combined FP measurement and MRI experiment in rat is presented in [13]. In addition, EEGs and electrocardiograms (ECG) may be utilized for triggering of external stimulation and fMRI, and in-magnet subject monitoring. MRI provides non-invasive high spatial resolution anatomical images of a rat brain (e.g., a 3 cm x 3 cm slice, 1.5 mm thick, imaged with 512 x 512 pixels) at the rate of one image in a few minutes. Low resolution functional brain images (e.g., same slice with 64 x 32 pixels) are acquired at the rate of one image per 100 ms. Both FP and EEG techniques have the same high time resolution (e.g., sampling rate 200 Hz – 12.5 kHz), but FP yields better spatial localization, since only a limited number of neural cells in the vicinity of the tip of the measurement electrode contributes to the signal, while EEG reflects electrical activity of a relatively large cortical area. FP measurements can thus be correlated both spatially and temporally with the MRI images. The analysis presented in this study is a critical part of the preparation for the work outlined above. Inmagnet electrical measurements cannot be analyzed without clear knowledge of the effects of the static magnetic field on the electrical measurements. This work also dictates what kind of signal analysis can be done online with MRI imaging, and to which extent the measured signals must be post-processed in order to account for disturbances, and further, if some of the planned analyses are prohibited by the disturbances. 2. MEASUREMENT SYSTEM 2.1. Animal Preparation We conducted these experiments on six male Kuopio Wistar rats (460 g – 580 g) anesthetized with 1.3 g/kg – 1.8 g/kg urethane depending of the reflex test done to assure the anesthesia. The Provincial Government of Eastern Finland (Approval No. 99-61/2002) has approved the methods with experimental animals used here. The ECG electrode was 0.25 mm of diameter oxidized silver wire, approximately 2 cm of which was im- planted subcutaneously (s.c.) close to the heart. A similar reference electrode was implanted s.c. on the back of the rat. For implanting the FP measurement electrode (0.05 mm of diameter insulated tungsten wire), scalp was first removed. Then a small bone window was drilled at 3.5 mm behind bregma, 2.5 mm left of the midline of the scull, and the electrode was lowered 2.2 mm into the brain from the cortical brain surface [14]. The electrode tip was aimed at CA1 region of the hippocampus, which also will be mostly used in our future experiments. Placement of the electrode was verified by observing a typical FP for the target structure. Effects of the static magnetic field are expected to be similar for measurements from anywhere in the brain, since the size of the rat brain is small compared to the dimensions of the static magnetic field. An FP measurement reference electrode and a ground electrode were similar to the ECG electrodes, and were bilaterally implanted s.c. to the neck of the rat. With three rats, we placed tungsten wire electrodes (3 mm of insulation was removed from the tip) to the cerebellum as reference and ground electrodes. For those rats, the electrodes served as reference electrodes for the ECG measurement as well. For one rat, the oxidized silver electrode was put near the nasal bone to serve as a reference electrode. For insertion into the magnet, the rat was attached to a custom made stereotaxic device, which fixes the head into a standard position. 2.2. ECG and FP Measurement Systems For the first two measurement sets, signals from the FP and ECG electrodes were taken to two separate battery powered amplifiers (DAM70-E, World Precision Instruments, Sarasota, FL, USA). The amplifiers were set to perform AC voltage measurements. The amplifiers have build-in filtering, and for ECG, amplification, high pass filter cutoff, and low pass filter cutoff were set to 1000, 10 Hz, and 100 Hz, respectively. For FP measurements, these amplifier settings were 1000, 0.1 Hz, and 100 Hz, respectively. The amplifiers were placed in the metal shielding room where the magnet was located. For the four other measurement sets, we used an inhouse made multi-channel differential amplifier for both FP and ECG measurements. The amplification factor was 1000. The high pass filter cutoff and low pass filter cutoff were fixed at 0.1 Hz and 5000 Hz, respectively. The amplifier was placed inside the metal shielding room of the magnet. The amplifier was powered by a Mascot power supply type 6328 (Mascot, UK) with ±12 V which was placed outside the metal shielding room. Signals were digitized at 1 kHz with 12-bit analog-todigital converters (DigiData, 1200 Series Interface, Axon Instruments, Inc., Union City, CA, USA), and read in a PC with Axoscope 9.0 program (Axon Instruments, Inc.) for initial display and storage. 2.3. MRI System The MRI system consists of a horizontal 4.7 T magnet (Magnex Scientific, Abingdon, UK) interfaced to a Varian UnityInova (Varian, Inc., Palo Alto, CA, USA) console. The imagining system contains a superconductive main magnet, producing a static main magnetic field B0, which cannot be turned off. A set of gradient magnetic field coils produce magnetic fields to correct possible B0 inhomogeneities and introduce time-varying magnetic gradient fields necessary for imaging. For example, gradient switching can be done in 250 µs with maximum magnetic flux density of 1.7 mT/cm. A transceiver coil transmits a radio frequency (RF) signal into the subject’s head to deviate net magnetization created by proton spins from the direction of B0 and subsequently receives the signals transmitted by the same protons while the magnetization realigns with the above-mentioned direction of B0. The whole system is located within a Faraday room for disturbance shielding. In the 4.7 T magnet, RF used in proton imaging is 200.15 MHz. Our maximum RF transmitter power is 1 kW, which can be fed into the transmitter coil, and which then produces a time-varying magnetic field B1 of approximate maximum flux density of 0.1 mT. During the measurements, the transmitter coil was placed directly above the subject’s head, and thus also above the FP measurement site, and was within 4 mm from the FP electrode connector. 2.4. Sources of Measurement Artifacts All of the MRI system components are expected to cause artifacts [15] to any electrical signals measured inside the magnet. Any magnetic field introduces a force on a moving charge. In addition, gradient switching and RF transmission are received by any measurement electrodes and wiring. Also, subject movement in B0, including movement of brain caused by heart beat and blood flow, causes artifacts [15,16]. In this work, skull movements were assumed negligible, since the rat was fixed in the stereotaxic device. Possible heart beat effects were analyzed from the electrical measurements. Artifact removal in combined ECG or EEG, and MRI measurements were studied in [16,17], respectively. For our planned research, it is sufficient to observe and analyze electrical measurements taken during the inherent delays between subsequent MRI images. For MRI at one image per second, the gradient coil and RF transmitter inactivity period is approximately 985 ms between images. Therefore, in this study we considered only the effects of the static magnetic field B0. 3. QUALITY OF IN-MAGNET ELECTRICAL MEASUREMENTS We can distinguish typical theta (3.5 Hz) and low frequency (0.7 Hz) oscillations from the signal measured in our typical field potential measurement in the hippocampus (Figure 1). These oscillations indicate neuronal activity during active and inactive brain states, respectively. In addition, gamma oscillations (37 Hz) were present in one measurement set on a distinct 2 Hz carrier oscillation (Figure 1) typically in the in-magnet measurements. Gamma oscillation peak can be seen also in Figure 2 in the in-magnet measurement. Although theta and low frequency oscillations do not occur at the same time, power spectral peaks from both oscillations types can be seen in Figure 3. since the measurement time was long enough (3 min) to include both states. Power spectral densities in Figures 3 and 4 are from different animals. Power spectral densities were calculated with Welch's averaged periodogram method with a Hanning window of 214 length. Overlapping of the windows were 50 %. In addition, in other measurements we can see clearly peaks at several different frequencies indicating changes in brain states (data not shown). However, additional frequency components at the theta frequency that we found in the in-magnet measurements (Figure 3) in one occasion may be linked with brain state changes and not with the static magnetic field, although the Müri et al. [15] observed similar additional peak close to the main frequency inside a magnet. Previous work by Müri group suggested that there was an artifact in human EEG signal caused by the heart cycle. We found such evidence only once in our FP measurements (Figure 4). This was the case when the reference electrode was placed near the nasal bone of the rat. In any other measurements, we did not find artifacts caused by simultaneous ECG measurement. Overall, the ECG in all of the measurements was clear and the heart rate, for example, could easily be calculated. We observed in our FP and ECG measurements with the DAM70-E amplifiers a 50 Hz artifact, which we could not isolate and remove. With the in-house made amplifier, we noticed the 50 Hz artifact only in the outside magnet measurements (Figure 2). All of the inmagnet measurements with the in-house made amplifier were free of the 50 Hz artifact. Appropriate design of the in-house made amplifier, good shielding, and close location of the preamplifiers to the recording site may have contributed to the excellent performance of the amplifier. 2 2 10 Power Spectral Density Power Spectral Density 10 0 10 −2 10 0 20 40 Frequency (Hz) 0 10 −2 10 60 0 20 40 Frequency (Hz) 60 Figure 2. Power spectra of the measured FP signals outside (left) and inside (right) magnetic resonance imaging magnet. 50 Hz artifact can be seen in the measurements outside the magnet. In the in-magnet measurement, gamma oscillations cause a spectral density peak near 30 Hz. 50 Power Spectral Density Power Spectral Density 50 40 30 20 10 0 0 1 2 3 Frequency (Hz) 4 40 30 20 10 0 0 5 1 2 3 4 5 Frequency (Hz) Figure 3. Power spectra of the measured FP signals outside (left) and inside (right) magnetic resonance imaging magnet. 0.4 0.2 0 Voltage (mV) Voltage (mV) 1 −1 −2 −3 0 0 −0.2 −0.4 0.2 0.4 0.6 Time (s) 0.8 1 −0.6 0 0.2 0.4 0.6 Time (s) 0.8 1 Figure 4. Artifact observed in only one field potential measurement (left) caused by electrocardiogram (right). 4. CONCLUSIONS We measured field potentials from the hippocampus of the rat and electrocardiograms inside and outside a magnetic resonance imaging magnet. We did not find any major differences in the oscillations between the outside and in-magnet measurements. We think that the changes seen in the frequency analysis are probably due to different states of the brain. It is hard to study only the effect of the static magnetic field because the sleep state of the rat was not consistent over the measurement set and over different rats, which made the comparisons very difficult and some times impossible. The right placement for the reference and ground electrodes seemed to be essential. The cerebellum turned out to be a good place for the electrodes even though it usually caused some bleeding. Post-processing of the signal is needed if we want to clear out all of the artifacts including the 50 Hz and artifacts caused by the MRI sequences. Foremost, we can conclude that the artifacts observed do not appear to be overwhelming compared to the signal and that we can easily recognize the different types of oscillations, which is necessary to our future FMRI studies. 5. ACKNOWLEDGMENTS The work of Joanna Tuppurainen and Jarno Tanskanen was funded by the Academy of Finland (decision numbers 201497 and 80323, respectively). Tanskanen’s literature grant from the Finnish Cultural Foundation of Northern Savo is greatly acknowledged. 6. REFERENCES [1] M. 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