Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model.

Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brain stem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low-beta and slow rhythm, as well as their interactions. Our model suggests that propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta-frequency spiking in thalamus (C-state), whereas in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha colocalizes to the peak of the slow oscillation; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brain stem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state.NEW & NOTEWORTHY GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We constructed a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brain stem neuromodulation.

Thalamocortical control of propofol phase-amplitude coupling.

The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.

Thalamic mechanisms underlying alpha-delta sleep with implications for fibromyalgia.

Alpha-delta sleep is the abnormal intrusion of alpha activity (8- to 13-Hz oscillations) into the delta activity (1- to 4-Hz oscillations) that defines slow-wave sleep. Alpha-delta sleep is especially prevalent in fibromyalgia patients, and there is evidence suggesting that the irregularities in the sleep of these patients may cause the muscle and tissue pain that characterizes the disorder. We constructed a biophysically realistic mathematical model of alpha-delta sleep. Imaging studies in fibromyalgia patients suggesting altered levels of activity in the thalamus motivated a thalamic model as the source of alpha activity. Since sodium oxybate helps to alleviate the symptoms of fibromyalgia and reduces the amount of alpha-delta sleep in fibromyalgia patients, we examined how changes in the molecular targets of sodium oxybate affected alpha-delta activity in our circuit. Our model shows how alterations in GABAB currents and two thalamic currents, Ih (a hyperpolarization-activated current) and a potassium leak current, transform a circuit that normally produces delta oscillations into one that produces alpha-delta activity. Our findings suggest that drugs that reduce Ih conductances and/or increase potassium conductances, without necessarily increasing GABAB conductances, might be sufficient to restore delta sleep. Furthermore, they suggest that delta sleep might be restored by drugs that preferentially target these currents in the thalamus; such drugs might have fewer side effects than drugs that act systemically.

Thalamocortical mechanisms for the anteriorization of α rhythms during propofol-induced unconsciousness.

As humans are induced into a state of general anesthesia via propofol, the normal alpha rhythm (8-13 Hz) in the occipital cortex disappears and a frontal alpha rhythm emerges. This spatial shift in alpha activity is called anteriorization. We present a thalamocortical model that suggests mechanisms underlying anteriorization. Our model captures the neural dynamics of anteriorization when we adjust it to reflect two key actions of propofol: its potentiation of GABA and its reduction of the hyperpolarization-activated current Ih. The reduction in Ih abolishes the occipital alpha by silencing a specialized subset of thalamocortical cells, thought to generate occipital alpha at depolarized membrane potentials (>-60 mV). The increase in GABA inhibition imposes an alpha timescale on both the cortical and thalamic portions of the frontal component that are reinforced by reciprocal thalamocortical feedback. Anteriorization can thus be understood as a differential effect of anesthetic drugs on thalamic nuclei with disparate spatial projections, i.e.: (1) they disrupt the normal, depolarized alpha in posterior-projecting thalamic nuclei while (2) they engage a new, hyperpolarized alpha in frontothalamic nuclei. Our model generalizes to other anesthetics that include GABA as a target, since the molecular targets of many such anesthetics alter the model dynamics in a manner similar to that of propofol.

Thalamic model of awake alpha oscillations and implications for stimulus processing.

We describe a unique conductance-based model of awake thalamic alpha and some of its implications for function. The full model includes a model for a specialized class of high-threshold thalamocortical cells (HTC cells), which burst at the alpha frequency at depolarized membrane potentials (~-56 mV). Our model generates alpha activity when the actions of either muscarinic acetylcholine receptor (mAChR) or metabotropic glutamate receptor 1 (mGluR1) agonists on thalamic reticular (RE), thalamocortical (TC), and HTC cells are mimicked. In our model of mGluR1-induced alpha, TC cells are equally likely to fire during any phase of alpha, consistent with in vitro experiments. By contrast, in our model of mAChR-induced alpha, TC cells tend to fire either at the peak or the trough of alpha, depending on conditions. Our modeling suggests that low levels of mGluR1 activation on a background of mAChR agonists may be able to initiate alpha activity that biases TC cells to fire at certain phases of alpha, offering a pathway for cortical control. If we introduce a strong stimulus by increasing the frequency of excitatory postsynaptic potentials (EPSPs) to TC cells, an increase in alpha power is needed to mimic the level of phasing of TC cells observed in vivo. This increased alpha power reduces the probability that TC cells spike near the trough of alpha. We suggest that mAChR-induced alpha may contribute to grouping TC activity into discrete perceptual units for processing, whereas mGluR1-induced alpha may serve the purpose of blocking unwanted stimuli from reaching the cortex.

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

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.

Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment.

The disorganized symptoms of schizophrenia, including severely disordered thought patterns, may be indicative of a problem with the construction and maintenance of cell assemblies during sensory processing and attention. The gamma and beta frequency bands (15-70 Hz) are believed relevant to such processing. This paper addresses the results of an experimental examination of the cortical response of 12 schizophrenia patients and 12 control subjects when presented with auditory click-train stimuli in the gamma/beta frequency band during measurement using magnetoencephalography (MEG), as well as earlier work by Kwon et al. These data indicate that control subjects show an increased 40-Hz response to both 20- and 40-Hz stimulation as compared with patients, whereas schizophrenic subjects show a preference for 20-Hz response to the same driving frequencies. In this work, two computational models of the auditory cortex are constructed based on postmortem studies that indicate cortical interneurons in schizophrenic subjects have decreased GAT-1 (a GABA transporter) and GAD(67) (1 of 2 enzymes responsible for GABA synthesis). The models transition from control to schizophrenic frequency response when an extended inhibitory decay time is introduced; this change captures a possible effect of these GABA alterations. Modeling gamma/beta range auditory entrainment in schizophrenia provides insight into how biophysical mechanisms can impact cognitive function. In addition, the study of dynamics that underlie auditory entrainment in schizophrenia may contribute to the understanding of how gamma and beta rhythms impact cognition in general.

Network architecture, receptive fields, and neuromodulation: computational and functional implications of cholinergic modulation in primary auditory cortex.

Two fundamental issues in auditory cortical processing are the relative importance of thalamocortical versus intracortical circuits in shaping response properties in primary auditory cortex (ACx), and how the effects of neuromodulators on these circuits affect dynamic changes in network and receptive field properties that enhance signal processing and adaptive behavior. To investigate these issues, we developed a computational model of layers III and IV (LIII/IV) of AI, constrained by anatomical and physiological data. We focus on how the local and global cortical architecture shape receptive fields (RFs) of cortical cells and on how different well-established cholinergic effects on the cortical network reshape frequency-tuning properties of cells in ACx. We identify key thalamocortical and intracortical circuits that strongly affect tuning curves of model cortical neurons and are also sensitive to cholinergic modulation. We then study how differential cholinergic modulation of network parameters change the tuning properties of our model cells and propose two different mechanisms: one intracortical (involving muscarinic receptors) and one thalamocortical (involving nicotinic receptors), which may be involved in rapid plasticity in ACx, as recently reported in a study by Fritz and coworkers.