Neural correlate of resting-state functional connectivity under α2 adrenergic receptor agonist, medetomidine
Introduction
Spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal at resting state enable the detection of intrinsic brain network and functional connectivity. These coherent hemodynamic fluctuations are observed in the low frequencies (< 0.1 Hz) of the BOLD and CBF signals (Biswal et al., 1995, Chuang et al., 2008). While the hemodynamic footprint of such intrinsic networks has been extensively investigated, the underlying electrophysiological signature remains elusive (Laufs et al., 2003b, Leopold and Logothetis, 2003, Nir et al., 2008). Electrophysiology, which directly relates dynamic postsynaptic activity in the cerebral cortex, has been used to observe synchronization across frequency bands in large-scale functional networks. How resting-state MRI (rsMRI) recordings translate to electrophysiology readings is of uttermost interest.
Most studies to date have investigated the correlation between electroencephalogram (EEG) and the resting-state BOLD signal. The α-band activity in the occipital lobe (Goldman et al., 2002, Moosmann et al., 2003, Scheeringa et al., 2012) and frontal and parietal cortices (Laufs et al., 2003a) of human subjects negatively correlated with rsMRI at the time when global α power correlated inversely with the thalamic rate of glucose metabolism (Larson et al., 1998, Lindgren et al., 1999). Functional coupling of the regional BOLD signal and EEG oscillations in beta and gamma frequency ranges was also found in regions comprising the default mode network (DMN) and the anterior thalamic nucleus (Michels et al., 2010). Increased α and β power is related to decreased functional connectivity while gamma power positively correlated with BOLD connectivity between specific brain areas (Tagliazucchi et al., 2012). In isoflurane anesthetized non-human primates, rsMRI fluctuations were found to positively correlate with gamma-band local field potential (Shmuel and Leopold, 2008). In rodents, high correlation between rsMRI signals and delta band oscillations under increasing α-chloralose dosages was identified (Lu et al., 2007). Ultra-slow frequency EEG signal (< 0.5 Hz) was explored and found to have high regional correlations with the low-frequency BOLD signal (Pan et al., 2011). Similar correlation with ultra-slow EEG has also been reported in non-human primates, while BOLD positively correlated with the gamma power as well (He et al., 2008). In human, intracranial local field potential in interhemispheric auditory cortex showed correlation between BOLD and gamma band power (Nir et al., 2007).
Where the use of anesthesia is unavoidable in most electrophysiology and fMRI studies in animals, the choice of anesthesia and type of anesthetic used are likely to significantly affect spontaneous brain activity and neurovascular coupling. For example, a strong dependency of coherent BOLD fluctuations on isoflurane levels was seen in rats (Liu et al., 2011). Masamoto et al. showed that CBF increased with increasing isoflurane dosages while the coupling between evoked potential and CBF varied (Masamoto et al., 2009). The diverse effects of different anesthesia/sedatives and how they critically interfere with the pathway of neurovascular coupling have been well documented (Masamoto and Kanno, 2012). This could confound the interpretation of functional connectivity linking to the underlying electrophysiological mechanism.
Medetomidine, an α2-adrenergic receptor agonist, has been used as a sedative in functional connectivity MRI studies in rodents (Adamczak et al., 2010, Pawela et al., 2009, Weber et al., 2006). In previous study, we showed that medetomidine suppressed resting-state functional connectivity in receptor-dominating regions dosage-dependently but with no effect on somatosensory BOLD activation (Nasrallah et al., 2012). As a vasoconstrictor, medetomidine may affect the neurovascular coupling. To further understand the neural correlate of the medetomidine on functional connectivity, we conducted electrophysiology measurements of somatosensory evoked potential (SEP) and resting EEG under different medetomidine dosages and correlated with the BOLD signals under the same conditions. We hypothesized that the coupling between electrophysiology and BOLD signal is not changed by medetomidine and BOLD signal can reflect the underlying functional synchrony in the brain. The coupling between EEG and fMRI was further compared under a common anesthetic, isoflurane, to understand the specificity of the medetomidine effect.
Section snippets
Animal preparation
All experiments were conducted in compliance with guidelines set forth by the institutional animal care and use committees of the Biomedical Sciences Institutes (A*STAR, Singapore). Twenty male Wistar rats weighing 300–400 g were used in the MRI study. A separate thirty male Wistar rats (300–400 g) were used in the EEG study. The rats were placed in a gas anesthesia induction chamber and 3% isoflurane was induced in a mixture of air and O2 gases (40% O2) via a calibrated vaporizer. Rats were
BOLD activation and SEP under medetomidine
Consistent SEPs were obtained in the contralateral S1FL cortex following a stimulation of 3 mA with a range of frequencies from 3, 5, 7, 9, to 12 Hz. Fig. 1 shows the stimulus frequency dependent SEPs at 0.1, 0.2 and 0.3 mg/kg/h of medetomidine. Average SEP under 0.1 and 0.3 mg/kg/h medetomidine showed similar responses with no significant difference in the peak amplitude or total interval at the same stimulus frequency (Figs. 1a and b). Highest SEP integrals were seen between 3 and 7 Hz. No
Discussion
Tight coupling was found between the EEG and BOLD signals recorded from the rat somatosensory cortex under various doses of medetomidine sedation or isoflurane anesthesia. Although medetomidine reduces CBF and isoflurane increases CBF dose dependently, the linear EEG–BOLD correlations suggest that the stimulus evoked and resting-state hemodynamic fluctuations observed are representative of neural activity rather than non-neuronal phenomena. Especially, this study confirmed our previous finding
Conclusion
The tight and unaffected neurovascular coupling observed between evoked potential and BOLD activation under medetomidine sedation suggests that the spontaneous BOLD fluctuations may reflect altered neural oscillation, especially in the gamma band. This supports the neuronal origin of functional connectivity measured by fMRI. Further study, especially using concurrent measurement of BOLD and electrophysiology, will be needed to understand the link with gamma synchrony. Unlike medetomidine,
Acknowledgments
The work was supported by the Intramural Research Program of the Singapore Bioimaging Consortium, Biomedical Sciences Institutes, Agency for Science, Technology and Research (A*STAR), Singapore.
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