Thalamocortical model for a propofol-induced α-rhythm associated with loss of consciousness

Abstract

Recent data reveal that the general anesthetic propofol gives rise to a frontal α-rhythm at dose levels sufficient to induce loss of consciousness. In this work, a computational model is developed that suggests the network mechanisms responsible for such a rhythm. It is shown that propofol can alter the dynamics in thalamocortical loops, leading to persistent and synchronous α-activity. The synchrony that forms in the cortex by virtue of the involvement of the thalamus may impede responsiveness to external stimuli, thus providing a correlate for the unconscious state.general anesthesia | oscillations | global coherence | GABA T he anesthetic agent propofol (2,6-di-isopropylphenol) is known to elicit frontal α-rhythms (10-13 Hz) in the EEG (1). Recent data analyses (2, 3) suggest that this rhythm, which is spatially distinct from the classic occipital α-rhythm, is highly coherent across electrodes. Moreover, its appearance is well correlated with the anesthetic-induced loss of consciousness. Although much is known about the molecular actions of propofol, an understanding of the network mechanisms that lead to such EEG-level phenomena remains absent. The present work uses computational models to elucidate some of these mechanisms. It builds on the work of McCarthy et al. (4), in which a model of cortical networks was used to reveal dynamic changes that may underlie the paradoxical excitation associated with low doses of propofol. Here, these mechanisms are incorporated into a broader thalamocortical model that accounts for the aforementioned EEG features associated with the administration of higher anesthetic doses.The model suggests that propofol, via its potentiation of the GABA A synaptic current, effectively enhances the strength of projections from the cortex to thalamus, resulting in a wellcoordinated thalamocortical α-oscillation. We consider a network of cortical pyramidal (E) cells and interneurons (INs), coupled with thalamocortical relay (TC) and thalamic reticular (RE) neurons. Reciprocal projections between the E and TC cells form an excitatory thalamocortical loop. Propofol enters the model as an increase in the conductance and decay time of the GABA A inhibitory current. At low levels of the drug, the cortical part of the model produces the expected paradoxical excitation, whereas the thalamic part fires at a slower irregular rate. Increasing the inhibition to a level commensurate with a higher dose of the drug causes cortical cell firing to slow into the α-range. Importantly, this also changes the thalamic substrate by increasing the inhibition delivered by the RE neurons to the TC neurons, producing rebound spiking. Thus, the cortical input to the thalamus is effectively enhanced, enabling the latter to be recruited into the same α-frequency. Because the reticular nucleus innervates widely, it has the capacity to synchronize thalamic oscillations. These oscillations then manifest coherently at the cortex through the thalamocortical loop. Thus, the model produces a coherent propofol-induced α-rhyth...

A neurophysiological–metabolic model for burst suppression

“…A similar feature has been observed during burst suppression induced by isoflurane general anesthesia, in which slow-wave and delta activity persists during the burst epochs (11). The propofol-induced alpha is thought to involve potentiation of gamma aminobutyric acid (GABA) inhibitory currents in thalamocortical loops (20,21). The recovery of these mechanisms during bursts suggests that a more global dynamic perturbation, (i.e., not simply an increase in GABA, must be responsible for creating the epochs of suppression).…”

“…We demonstrate the main result using a purely cortical network consisting of reciprocally coupled interneurons and pyramidal cells. As shown previously (20,37), such a network can be used to explain the progressive reduction in frequency of EEG oscillations observed during induction of general anesthesia via propofol. The mechanism in those models was a drug-induced potentiation of GABA A inhibitory postsynaptic potentials.…”

“…3. The neuronal network consists of cortical pyramidal neurons and interneurons that produce neuronal oscillations on timescales commensurate with the EEG observed during general anesthesia (19,20). To this network, we add dynamics associated with ATP consumption, in the form of the sodium-ATP pump, which is thought to be the major consumer of cerebral ATP (29,33).…”

Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

“…Different cortical layers in prelimbic cortex display different connectivity patterns with thalamus and other cortical and subcortical areas. Also, the model put forward by Ching et al (14) assumed a generic prefrontal layer 5 neuron. Therefore, we investigated the possibility of different layers being differentially affected by propofol.…”

“…Electroencephalogram (EEG) recordings in humans during gradual induction of unconsciousness with propofol show the appearance of frontal β oscillations (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) at the onset of sedation, followed by the appearance of coherent frontal α (8-12 Hz) oscillations (7)(8)(9)(10) and widespread slow (0.1-1 Hz) and δ (1-4 Hz) oscillations (7,11,12) when subjects no longer respond to sensory stimuli. Biophysical models of neuronal dynamics have shown that whereas α and β oscillations can be generated by propofol's actions in cortex alone (13), coherent α oscillations require the participation of both thalamus and cortex (14). Imaging studies in humans have shown that propofol disrupts functional relationships between cortex and thalamus, eliciting a greater degree of disruption between cortex and higher-order thalamic nuclei compared with first-order nuclei (15).…”