Elsevier

NeuroImage

Volume 84, 1 January 2014, Pages 27-34
NeuroImage

Neural correlate of resting-state functional connectivity under α2 adrenergic receptor agonist, medetomidine

https://doi.org/10.1016/j.neuroimage.2013.08.004Get rights and content

Highlights

  • SEP correlate similarly with BOLD at all MED doses indicate same neurovascular coupling.

  • Resting gamma coherence suppressed but not power at higher MED dosages.

  • Both activity and connectivity decreased under general anesthesia, isoflurane.

  • Dissociated connectivity but unaltered activity suggest mechanism of sedative effect of MED.

Abstract

Correlative fluctuations in functional MRI (fMRI) signals across the brain at rest have been taken as a measure of functional connectivity, but the neural basis of this resting-state MRI (rsMRI) signal is not clear. Previously, we found that the α2 adrenergic agonist, medetomidine, suppressed the rsMRI correlation dose-dependently but not the stimulus evoked activation. To understand the underlying electrophysiology and neurovascular coupling, which might be altered due to the vasoconstrictive nature of medetomidine, somatosensory evoked potential (SEP) and resting electroencephalography (EEG) were measured and correlated with corresponding BOLD signals in rat brains under three dosages of medetomidine. The SEP elicited by electrical stimulation to both forepaws was unchanged regardless of medetomidine dosage, which was consistent with the BOLD activation. Identical relationship between the SEP and BOLD signal under different medetomidine dosages indicates that the neurovascular coupling was not affected. Under resting state, EEG power was the same but a depression of inter-hemispheric EEG coherence in the gamma band was observed at higher medetomidine dosage. Different from medetomidine, both resting EEG power and BOLD power and coherence were significantly suppressed with increased isoflurane level. Such reduction was likely due to suppressed neural activity as shown by diminished SEP and BOLD activation under isoflurane, suggesting different mechanisms of losing synchrony at resting-state. Even though, similarity between electrophysiology and BOLD under stimulation and resting-state implicates a tight neurovascular coupling in both medetomidine and isoflurane. Our results confirm that medetomidine does not suppress neural activity but dissociates connectivity in the somatosensory cortex. The differential effect of medetomidine and its receptor specific action supports the neuronal origin of functional connectivity and implicates the mechanism of its sedative effect.

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.

References (54)

  • Y. Nir et al.

    Coupling between Neuronal firing rate, gamma LFP, and BOLD fMRI is related to interneuronal correlations

    Curr. Biol.

    (2007)
  • C. Pawela et al.

    A protocol for use of medetomidine anesthesia in rats for extended studies using task-induced BOLD contrast and resting-state functional connectivity

    NeuroImage

    (2009)
  • E. Tagliazucchi et al.

    Automatic sleep staging using fMRI functional connectivity data

    NeuroImage

    (2012)
  • R. Weber et al.

    A fully noninvasive and robust experimental protocol for longitudinal fMRI studies in the rat

    NeuroImage

    (2006)
  • F. Zhao et al.

    BOLD study of stimulation-induced neural activity and resting-state connectivity in medetomidine-sedated rat

    NeuroImage

    (2008)
  • M. Alkire et al.

    Consciousness and anesthesia

    Science

    (2008)
  • J.F. Antognini et al.

    Isoflurane blunts electroencephalographic and thalamic–reticular formation responses to noxious stimulation in goats

    Anesthesiology

    (1999)
  • M. Bartos et al.

    Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

    Nat. Rev. Neurosci.

    (2007)
  • B. Biswal et al.

    Functional connectivity in the motor cortex of resting human brain using echo-planar MRI

    Magn. Reson. Med.

    (1995)
  • M. Bruyns-Haylett et al.

    The resting-state neurovascular coupling relationship: rapid changes in spontaneous neural activity in the somatosensory cortex are associated with haemodynamic fluctuations that resemble stimulus-evoked haemodynamics

    Eur. J. Neurosci.

    (2013)
  • G. Buzsáki et al.

    Noradrenergic control of thalamic oscillation: the role of α-2 receptors

    Eur. J. Neurosci.

    (1991)
  • A. Draguhn et al.

    Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro

    Nature

    (1998)
  • A. Engel et al.

    Role of the temporal domain for response selection and perceptual binding

    Cereb. Cortex

    (1997)
  • A. Fisahn et al.

    Distinct roles for the kainate receptor subunits GluR5 and GluR6 in kainate-induced hippocampal gamma oscillations

    J. Neurosci.

    (2004)
  • R. Goldman et al.

    Simultaneous EEG and fMRI of the alpha rhythm

    NeuroReport

    (2002)
  • C. Gray et al.

    Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • B. He et al.

    Electrophysiological correlates of the brain's intrinsic large-scale functional architecture

    Proc. Natl. Acad. Sci. U. S. A.

    (2008)
  • Cited by (42)

    • Functional networks and network perturbations in rodents

      2017, NeuroImage
      Citation Excerpt :

      At a low dose, such as 1–1.5%, a strong focal connectivity pattern can be obtained, although with suppressed thalamocortical connectivity (Bukhari et al., 2017; Grandjean et al., 2014a; Hutchison et al., 2014; Nasrallah et al., 2014a). Isoflurane has strong dosage-dependent effect on RSNs with reduced or complete loss of bilateral FC at high dose due to its suppression of both spontaneous activity and synchrony (Nasrallah et al., 2014a; Wang et al., 2011). A major complication in terms of RSNs is that isoflurane could induce burst-suppression activity across the brain at mid-to-high dose (e.g., >1.8% in rats) and hence could lead to a strong global correlation (Kalthoff et al., 2013; Liu et al., 2011; Liu et al., 2013b; Williams et al., 2010).

    • Altered regional connectivity reflecting effects of different anaesthesia protocols in the mouse brain

      2017, NeuroImage
      Citation Excerpt :

      Based on the observed long-range FC, CBV, action mode of anaesthetics and distribution density of specific receptors, Grandjean et al. concluded that contributions of CBV was minor to the rs-fMRI results (Grandjean et al., 2014a). The marginal effects of cerebrovascular parameters on BOLD signals are in agreement with other rodent studies using different agents and/or electrophysiological techniques, confirming that BOLD fMRI signals reflect neuronal activity rather than vascular (Nasrallah et al., 2014a; Nasrallah et al., 2014b; Schroeter et al., 2016). These reports suggest that contributions of vascular to regional connectivity should also remain minor compared to the modulation of receptor systems under the anaesthetic regimens investigated.

    View all citing articles on Scopus
    View full text