Norepinephrine Infusion into Nucleus Basalis Elicits Microarousal in Desflurane-anesthetized Rats

Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Anesthesiology (Impact Factor: 5.88). 07/2011; 115(4):733-42. DOI: 10.1097/ALN.0b013e31822c5ee1
Source: PubMed


The nucleus basalis of Meynert of the basal forebrain has been implicated in the regulation of the state of consciousness across normal sleep-wake cycles. Its role in the modulation of general anesthesia was investigated.
Rats were chronically implanted with bilateral infusion cannulae in the nucleus basalis of Meynert and epidural electrodes to record the electroencephalogram in frontal and visual cortices. Animals were anesthetized with desflurane at a concentration required for the loss of righting reflex (4.6 ± 0.5%). Norepinephrine (17.8 nmol) or artificial cerebrospinal fluid was infused at 0.2 μl/min (1 μl total). Behavioral response to infusion was measured by scoring the orofacial, limb, and head movements, and postural changes.
Behavioral responses were higher after norepinephrine (2.1 ± 1) than artificial cerebrospinal fluid (0.63 ± 0.8) infusion (P < 0.01, Student t test). Responses were brief (1-2 min), repetitive, and more frequent after norepinephrine infusion (P < 0.0001, chi-square test). Electroencephalogram delta power decreased after norepinephrine in frontal (70 ± 7%) but not in visual cortex (P < 0.05, Student t test). Simultaneously, electroencephalogram cross-approximate entropy between frontal and visual cortices increased from 3.17 ± 0.56 to 3.85 ± 0.29 after norepinephrine infusion (P < 0.01, Student t test). Behavioral activation was predictable by the decrease in frontal delta power (logistic regression, P < 0.05).
Norepinephrine infusion into the nucleus basalis of Meynert can modulate anesthetic depth presumably by ascending activation of the cortex. The transient nature of the responses suggests a similarity with microarousals normally observed during natural sleep, and may imply a mechanism for transient awareness under light anesthesia.


Available from: Siveshigan Pillay, Jan 05, 2014
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    • "We used a homemade, high-impedance, MR and biocompatible carbon fiber electrode to stimulate the PnO (Dunn et al., 2009; Jupp et al., 2006; Kitzmiller et al., 2006; Tallgren et al., 2005). As anticipated, electrical stimulation of the PnO induced an attenuation of d and h band power, an indication of cortical desynchronization ( Jones, 2004; Pillay et al., 2011). A concomitant increase in power at higher frequencies was not observed presumably because the rats continuously received isoflurane anesthesia, and the relatively low intensity of PnO stimulation used did not elicit any behavioral changes. "
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    ABSTRACT: Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodulatory networks. Manipulating key components of the ascending arousal system (AAS) via deep brain stimulation may help facilitate global arousal in anesthetized animals. Here we test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) under light isoflurane anesthesia associated with loss of consciousness leads to cortical arousal and specific changes in blood-oxygenation-level dependent (BOLD) functional connectivity (FC) of the brain. BOLD signals were acquired simultaneously with frontal epidural EEG before and after PnO stimulation. Whole-brain FC was mapped using correlation analysis with seeds in major centers of the AAS. PnO stimulation produced cortical desynchronization, a decrease in δ-and θ-band power, and an increase in approximate entropy. Significant increases in FC after PnO stimulation occurred between the left nucleus Basalis of Meynert (NBM) as seed and numerous regions of the paralimbic network. Smaller increases in FC were present between the central medial n. of thalamus and retrosplenium seeds and the left caudate putamen and NBM. The results suggest that, during light anesthesia, PnO stimulation preferentially modulates basal forebrain-paralimbic networks. We speculate that this may be a reflection of disconnected awareness.
    Brain Connectivity 08/2014; 4(7). DOI:10.1089/brain.2014.0254
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    • "Taken together, our results support a role for the PnO in modulating cortical state and information integration during both spontaneous ongoing activity and visual stimulation. Future work could focus on pairing other sensory modalities to cortical state via manipulations of the AAS from multiple target sites, including the hypothalamus (Kelz et al., 2008) or basal forebrain (Pillay et al., 2011). These studies should contribute to a better understanding of the neuronal interaction of anesthetics and the AAS in modulating cortical information integration and the state of consciousness. "
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    ABSTRACT: States of consciousness have been associated with information integration in the brain as modulated by anesthesia and the ascending arousal system. The present study was designed to test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) can augment information integration in the cerebral cortex of anesthetized rats. Extracellular unit activity and local field potentials were recorded in freely moving animals from parietal association (PtA) and secondary visual (V2) cortices via chronically implanted microwire arrays at three levels of anesthesia produced by desflurane: 3.5, 4.5, and 6.0% (where 4.5% corresponds to that critical for the loss of consciousness). Information integration was characterized by integration (multiinformation) and interaction entropy, estimated from the statistical distribution of coincident spike patterns. PnO stimulation elicited electrocortical activation as indicated by the reductions in δ- and θ-band powers at the intermediate level of anesthesia. PnO stimulation augmented integration from 1.13 ± 0.03 to 6.12 ± 1.98 × 10(3) bits and interaction entropy from 0.44 ± 0.11 to 2.18 ± 0.72 × 10(3) bits; these changes were most consistent in the PtA at all desflurane concentrations. Stimulation of the retina with discrete light flashes after PnO stimulation elicited an additional 166 ± 25 and 92 ± 12% increase in interaction entropy in V2 during light and intermediate levels. The results suggest that the PnO may modulate spontaneous ongoing and sensory stimulus-related cortical information integration under anesthesia.
    Frontiers in Integrative Neuroscience 02/2014; 8:8. DOI:10.3389/fnint.2014.00008
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    • "The intralaminar and medial thalamic nuclei play important roles in enabling the conscious state (Alkire et al., 2000; Schiff, 2008; Schiff and Plum, 2000; Tononi, 2010). Pharmacological stimulation of the medial thalamus, hypothalamus and basal forebrain components can facilitate awakening from sleep and anesthesia (Alkire et al., 2007; Devor and Zalkind, 2001; Franks, 2008; Pillay et al., 2011; Reiner et al., 2007). Certain anesthetic agents may target components of these systems and the disruption of these pathways can lead to unconsciousness (Franks, 2008; Lu et al., 2008; Zecharia and Franks, 2009). "
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    ABSTRACT: The dose-dependent effects of anesthetics on brain functional connectivity are incompletely understood. Resting-state functional magnetic resonance imaging (rsfMRI) is widely used to assess the functional connectivity in humans and animals. Propofol is an anesthetic agent with desirable characteristics for functional neuroimaging in animals but its dose-dependent effects on rsfMRI functional connectivity have not been determined. Here we tested the hypothesis that brain functional connectivity undergoes specific changes in distinct neural networks at anesthetic depths associated with loss of consciousness. We acquired spontaneous blood oxygen level-dependent (BOLD) signals simultaneously with electroencephalographic (EEG) signals from rats under steady-state, intravenously administered propofol at increasing doses from light sedation to deep anesthesia (20, 40, 60, 80, and 100 mg/kg/h iv). Power spectra and burst suppression ratio were calculated from the EEG to verify anesthetic depth. Functional connectivity was determined from the whole brain correlation of BOLD data in regions of interest followed by a segmentation of the correlation maps into anatomically defined regional connectivity. We found that propofol produced multiphasic, dosedependent changes in functional connectivity of various cortical and subcortical networks. Cluster analysis predicted segregation of connectivity into two cortical and two subcortical clusters. In one cortical cluster (somatosensory and parietal), the early reduction in connectivity was followed by transient reversal; in the other cluster (sensory, motor and cingulate/retrosplenial), this rebound was absent. The connectivity of the subcortical cluster (brainstem, hippocampal and caudate) was strongly reduced, whereas that of another (hypothalamus, medial thalamus and n. Basalis) did not. Subcortical connectivity increased again in deep anesthesia associated with EEG burst suppression. Regional correlation analysis confirmed the breakdown of connectivity within and between specific cortical and subcortical networks with deepening propofol anesthesia. Cortical connectivity was suppressed before subcortical connectivity at a critical propofol dose associated with loss of consciousness.
    NeuroImage 07/2013; 83. DOI:10.1016/j.neuroimage.2013.07.003 · 6.36 Impact Factor
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