Mircea Steriade

Corticothalamic resonance, states of vigilance and mentation

During various states of vigilance, brain oscillations are grouped together through reciprocal connections between the neocortex and thalamus. The coherent activity in corticothalamic networks, under the control of brainstem and forebrain modulatory systems, requires investigations in intact-brain animals. During behavioral states associated with brain disconnection from the external world, the large-scale synchronization of low-frequency oscillations is accompanied by the inhibition of synaptic transmission through thalamocortical neurons. Despite the coherent oscillatory activity, on the functional side there is dissociation between the thalamus and neocortex during slow-wave sleep. While dorsal thalamic neurons undergo inhibitory processes due to the prolonged spike-bursts of thalamic reticular neurons, the cortex displays, periodically, a rich spontaneous activity and preserves the capacity to process internally generated signals that dominate the state of sleep. In vivo experiments using simultaneous intracellular recordings from thalamic and cortical neurons show that short-term plasticity processes occur after prolonged and rhythmic spike-bursts fired by thalamic and cortical neurons during slow-wave sleep oscillations. This may serve to support resonant phenomena and reorganize corticothalamic circuitry, determine which synaptic modifications, formed during the waking state, are to be consolidated and generate a peculiar kind of dreaming mentation. In contrast to the long-range coherent oscillations that occur at low frequencies during slow-wave sleep, the sustained fast oscillations that characterize alert states are synchronized over restricted territories and are associated with discrete and differentiated patterns of conscious events.

Neuronal Plasticity in Thalamocortical Networks during Sleep and Waking Oscillations

Spontaneous brain oscillations during states of vigilance are associated with neuronal plasticity due to rhythmic spike bursts and spike trains fired by thalamic and neocortical neurons during low-frequency rhythms that characterize slow-wave sleep and fast rhythms occurring during waking and REM sleep. Intracellular recordings from thalamic and related cortical neurons in vivo demonstrate that, during natural slow-wave sleep oscillations or their experimental models, both thalamic and cortical neurons progressively enhance their responsiveness. This potentiation lasts for several minutes after the end of oscillatory periods. Cortical neurons display self-sustained activity, similar to responses evoked during previous epochs of stimulation, despite the fact that thalamic neurons remain under a powerful hyperpolarizing pressure. These data suggest that, far from being a quiescent state during which the cortex and subcortical structures are globally inhibited, slow-wave sleep may consolidate memory traces acquired during wakefulness in corticothalamic networks. Similar phenomena occur as a consequence of fast oscillations during brain-activated states.

Spatiotemporal analysis of local field potentials and unit discharges in cat cerebral cortex during natural wake and sleep states.

The electroencephalogram displays various oscillation patterns during wake and sleep states, but their spatiotemporal distribution is not completely known. Local field potentials (LFPs) and multiunits were recorded simultaneously in the cerebral cortex (areas 5–7) of naturally sleeping and awake cats. Slow-wave sleep (SWS) was characterized by oscillations in the slow (<1 Hz) and delta (1–4 Hz) frequency range. The high-amplitude slow-wave complexes consisted in a positivity of depth LFP, associated with neuronal silence, followed by a sharp LFP negativity, correlated with an increase of firing. This pattern was of remarkable spatiotemporal coherence, because silences and increased firing occurred simultaneously in units recorded within a 7 mm distance in the cortex. During wake and rapid-eye-movement (REM) sleep, single units fired tonically, whereas LFPs displayed low-amplitude fast activities with increased power in fast frequencies (15–75 Hz). In contrast with the widespread synchronization during SWS, fast oscillations during REM and wake periods were synchronized only within neighboring electrodes and small time windows (100–500 msec). This local synchrony occurred in an apparent irregular manner, both spatially and temporally. Brief periods (<1 sec) of fast oscillations were also present during SWS in between slow-wave complexes. During these brief periods, the spatial and temporal coherence, as well as the relation between units and LFPs, was identical to that of fast oscillations of wake or REM sleep. These results show that natural SWS in cats is characterized by slow-wave complexes, synchronized over large cortical territories, interleaved with brief periods of fast oscillations, characterized by local synchrony, and of characteristics similar to that of the sustained fast oscillations of activated states.

Control of spatiotemporal coherence of a thalamic oscillation by corticothalamic feedback.

The mammalian thalamus is the gateway to the cortex for most sensory modalities. Nearly all thalamic nuclei also receive massive feedback projections from the cortical region to which they project. In this study, the spatiotemporal properties of synchronized thalamic spindle oscillations (7 to 14 hertz) were investigated in barbiturate-anesthetized cats, before and after removal of the cortex. After complete ipsilateral decortication, the long-range synchronization of thalamic spindles in the intact cortex hemisphere changed into disorganized patterns with low spatiotemporal coherence. Local thalamic synchrony was still present, as demonstrated by dual intracellular recordings from nearby neurons. In the cortex, synchrony was insensitive to the disruption of horizontal intracortical connections. These results indicate that the global coherence of thalamic oscillations is determined by corticothalamic projections.

Diffuse transmission by acetylcholine in the CNS.

Recent immunoelectron microscopic studies have revealed a low frequency of synaptic membrane differentiations on ACh (ChAT-immunostained) axon terminals (boutons or varicosities) in adult rat cerebral cortex, hippocampus and neostriatum, suggesting that, besides synaptic transmission, diffuse transmission by ACh prevails in many regions of the CNS. Cytological analysis of the immediate micro-environment of these ACh terminals, as well as currently available immunocytochemical data on the cellular and subcellular distribution of ACh receptors, is congruent with this view. At least in brain regions densely innervated by ACh neurons, a further aspect of the diffuse transmission paradigm is envisaged: the existence of an ambient level of ACh in the extracellular space, to which all tissue elements would be permanently exposed. Recent experimental data on the various molecular forms of AChE and their presumptive role at the neuromuscular junction support this hypothesis. As in the peripheral nervous system, degradation of ACh by the prevalent G4 form of AChE in the CNS would primarily serve to keep the extrasynaptic, ambient level of ACh within physiological limits, rather than totally eliminate ACh from synaptic clefts. Long-lasting and widespread electrophysiological effects imputable to ACh in the CNS might be explained in this manner. The notions of diffuse transmission and of an ambient level of ACh in the CNS could also be of clinical relevance, in accounting for the production and nature of certain cholinergic deficits and the efficacy of substitution therapies.

Neuronal activity during the sleep-waking cycle.

Abstract The pontine brain stem hypothesis of desynchronized sleep generation has been tested with cellular methods confirming its three principal tenets: Ascending activation is apparent in the increased discharge of almost every forebrain neuronal population that has been studied. The precise synaptic mechanisms mediating this net excitation have not been elucidated but tonic postsynaptic facilitation is likely to underlie EEG desynchronization while presynaptic inhibition and phasic postsynaptic facilitation are probably involved in PGO wave generation. Descending inhibition of spinal reflex activity has been documented and analyzed in detail. Indirect, but strong evidence favors the operation of tonic postsynaptic inhibition, phasic postsynaptic excitation and presynaptic inhibition in the genesis of atonia, muscle twitches, and phasic sensory changes respectively. Pontine control of some of these events has been strengthened by the satisfaction of criteria for executive neurones by the giant cells of the pontine reticular formation (FTG). These neurones may be directly responsible for phasic events including the REMs, muscle twitches, and PGO waves. They may be indirectly responsible for EEG desynchronization through recruitment of more rostral reticular elements. They are probably not responsible for the atonia which is more likely mediated by their more caudal medullary reticular congeners. The mechanism of periodic activation of the executive neurones in the FTG may be that of reciprocal interaction with other pontine level-setting elements for which the best candidates are those neurones in the locus coeruleus and dorsal raphe nucleus having activity curves reciprocal to those of the FTG. A precise neurophysiological and mathematical model of reciprocal interaction is described. The reciprocal interaction hypothesis of desynchronized sleep control finds independent confirmation in a vast array of pharmacological data on sleep. In particular, the following tenets of the hypothesis are supported: The executive elements of the pontine brain stem control system include the giant cells of the reticular formation (FTG). These cells are cholinoceptive and cholinergic. They excite postsynaptic follower elements including each other. When cholinergically activated, the FTG neurones cholinergically generated desynchronized sleep events including EEG desynchronization, eye movements, PGO and other phasic events. Drugs which enchance cholinergic synaptic transmission, especially when injected into the giant cell fields, enchance descynchronized sleep. By contrast, anticholinergic compounds suppress desynchronized sleep. Cholinergic agents may also show suppress desynchronized sleep when injected into the presumed level setting neuronal pools of the dorsal raphe nucleus (DRN) and locus coeruleus (LC). The level-setting elements for the FTG include cells in the DRN and LC. These cells may be aminergic and aminoceptive, inhibiting their postsynaptic followers including each other. When activated, they suppress desynchronized sleep events especially atonia and PGO activity. Drugs which enchance aminergic synaptic transmission tend to suppress desynchronized sleep. Antiaminergic agents tend to enhance desynchronized sleep. Aminergic drugs should suppress desynchronized sleep when injected into the pool of generator neurones in the FTG. The reciprocal interaction hypothesis thus orders an otherwise confusing pharmacological literature and gives rise to new and testable hypotheses of sleep-cycle regulation. The combination of chronic microelectrode recording and microinjection techniques may thus result in a precise cellular neuropharmacology of those reticular systems long thought to regulate sleep and other vegetative phenomena.

Reticularis thalami neurons revisited: activity changes during shifts in states of vigilance

This study tested the hypothesis that inhibitory actions are exerted by reticularis thalami (RE) neurons upon thalamocortical neurons. The RE neurons were recorded in the rostral pole and lateral districts of the nucleus, and were activated monosynaptically by cortical volleys. Thalamocortical neurons were identified antidromically in intralaminar and ventrolateral nuclei. During sleep with EEG synchronization, prolonged spike barrages of RE neurons extended over the whole spindle sequences. This result suggests that RE neurons are depolarized throughout spindle oscillations, whereas thalamocortical neurons show, simultaneously, long hyperpolarizations and short rebounds. During waking, parallelism rather than reciprocity was found between RE and thalamocortical neurons. Spontaneous discharge rates almost doubled in RE neurons on arousal from sleep, and the probability of cortically evoked short-latency discharges increased. The increase in spontaneous firing rates of RE neurons during natural arousal is consistent with their short-latency synaptic excitation by stimulating the rostral brain stem reticular formation after chronic degeneration of passing fibers. We suggest that RE cells inhibit GABAergic local-circuit cells, in addition to inhibiting thalamocortical neurons, and that different ratios of inhibitory effects are exerted by RE neurons upon these two cell classes during waking and sleep. We further suggest that, upon arousal, disinhibition of thalamocortical neurons (via the local- circuit neurons) outweighs direct inhibition of the thalamocortical neurons.

Coherent oscillations and short-term plasticity in corticothalamic networks

The neocortex and thalamus are a unified oscillatory machine. Different types of brain rhythms, which characterize various behavioral states, are combined within complex wave-sequences. During the stage of sleep that is associated with low-frequency and high-amplitude brain rhythms, the excitatory component of a cortically generated slow oscillation is effective in triggering thalamically generated rhythms and in increasing their spatiotemporal coherence over widespread territories. Thus, the study of coherent oscillations, as they appear naturally during states of vigilance in animals and humans, requires intact-brain preparations in which the neocortex and thalamus engage in a permanent dialog. Sleep oscillations are associated with rhythmic spike-bursts or spike-trains in thalamic and cortical neurons, which lead to persistent excitability changes consisting of increased depolarizing responses and decreased inhibitory responses. These short-term plasticity processes could be used to consolidate memory traces acquired during wakefulness, but can also lead to paroxysmal (hypersynchronous) episodes, similar to those observed in some epileptic seizures.

The K-complex: Its slow (<1-Hz) rhythmicity and relation to delta waves

The K-complex is a major graphoelement of sleep EEG. This report demonstrates that K-complexes emerge from a cortically generated slow(≤1-Hz) oscillation. Human EEG as well as cat cellular and field potential recordings converge into demonstrating that the K-complex results from a synchronized cortical network that imposes periodic excitatory and inhibitory actions on cortical neurons. We additionally show the correspondence between neuronal activities and the shape of the K-complex. Spectral analysis confirms the periodic recurrence of human K-complexes, with main peaks at 0.5 to 0.7 Hz. It is also shown that the spectral content in the delta band (1 to 4 Hz) is partially due to the shape and duration of the K-complex.

Arousal : Revisiting the reticular activating system

An area deep within the brain has been implicated in control of arousal or mental alertness. Two papers in this weeks issue of Science [Munk et al. (p. 271) and Castro-Alamancos and Connors (p. 274)] show how signals from this area, the midbrain reticular formation, change the physiology of the cortex, the part of the brain that governs higher functions. In his Perspective, Steriade traces the history of this field and discusses the significance of these results.