Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy.

BACKGROUND: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. METHODS: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time-frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. RESULTS: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha-gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). CONCLUSIONS: Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS.

Network alterations in temporal lobe epilepsy during non-rapid eye movement sleep and wakefulness.

OBJECTIVE: Investigate sleep and temporal lobe epilepsy (TLE) effects on brain networks derived from electroencephalography (EEG). METHODS: High-density EEG was recorded during non-rapid eye movement (NREM) sleep stage 2 (N2) and wakefulness in 23 patients and healthy controls (HC). Epochs without epileptic discharges were source-reconstructed in 72 brain regions and connectivity was estimated. We calculated network integration and segregation at global (global efficiency, GE; average clustering coefficient, avgCC) and hemispheric level. These were compared between groups across frequency bands and correlated with the individual proportion of wakefulness- or sleep-related seizures. RESULTS: At the global level, patients had higher delta GE, delta avgCC and theta avgCC than controls, irrespective of the vigilance state. During wakefulness, theta GE of patients was higher than controls and, for patients, theta GE during wakefulness was higher than during N2. Wake-to-sleep differences in TLE were notable only in the ipsilateral hemisphere. Only measures from wakefulness recordings correlated with the proportion of wakefulness- or sleep-related seizures. CONCLUSIONS: TLE network alterations are more prominent during wakefulness and at lower frequencies. Increased integration and segregation suggest a pathological 'small world' configuration with a possible inhibitory role. SIGNIFICANCE: Network alterations in TLE occur and are easier to detect during wakefulness.

Overnight changes in waking auditory evoked potential amplitude reflect altered sleep homeostasis in major depression.

OBJECTIVE: Sleep homeostasis is altered in major depressive disorder (MDD). Pre- to postsleep decline in waking auditory evoked potential (AEP) amplitude has been correlated with sleep slow wave activity (SWA), suggesting that overnight changes in waking AEP amplitude are homeostatically regulated in healthy individuals. This study investigated whether the overnight change in waking AEP amplitude and its relation to SWA is altered in MDD. METHOD: Using 256-channel high-density electroencephalography, all-night sleep polysomnography and single-tone waking AEPs pre- and postsleep were collected in 15 healthy controls (HC) and 15 non-medicated individuals with MDD. RESULTS: N1 and P2 amplitudes of the waking AEP declined after sleep in the HC group, but not in MDD. The reduction in N1 amplitude also correlated with fronto-central SWA in the HC group, but a comparable relationship was not found in MDD, despite equivalent SWA between groups. No pre- to postsleep differences were found for N1 or P2 latencies in either group. These findings were not confounded by varying levels of alertness or differences in sleep variables between groups. CONCLUSION: MDD involves altered sleep homeostasis as measured by the overnight change in waking AEP amplitude. Future research is required to determine the clinical implications of these findings.

Integrated information theory of consciousness: an updated account.

This article presents an updated account of integrated information theory of consciousness (IIT) and some of its implications. IIT stems from thought experiments that lead to phenomenological axioms and ontological postulates. The information axiom asserts that every experience is one out of many, i.e. specific - it is what it is by differing in its particular way from a large repertoire of alternatives. The integration axiom asserts that each experience is one, i.e. unified - it cannot be reduced to independent components. The exclusion axiom asserts that every experience is definite - it is limited to particular things and not others and flows at a particular speed and resolution. IIT formalizes these intuitions with three postulates. The information postulate states that only "differences that make a difference" from the intrinsic perspective of a system matter: a mechanism generates cause-effect information if its present state has specific past causes and specific future effects within a system. The integration postulate states that only information that is irreducible matters: mechanisms generate integrated information only to the extent that the information they generate cannot be partitioned into that generated within independent components. The exclusion postulate states that only maxima of integrated information matter: a mechanism specifies only one maximally irreducible set of past causes and future effects - a concept. A complex is a set of elements specifying a maximally irreducible constellation of concepts, where the maximum is evaluated at the optimal spatio-temporal scale. Its concepts specify a maximally integrated conceptual information structure or quale, which is identical with an experience. Finally, changes in information integration upon exposure to the environment reflect a system's ability to match the causal structure of the world. After introducing an updated definition of information integration and related quantities, the article presents some theoretical considerations about the relationship between information and causation and about the relational structure of concepts within a quale. It also explores the relationship between the temporal grain size of information integration and the dynamic of metastable states in the corticothalamic complex. Finally, it summarizes how IIT accounts for empirical findings about the neural substrate of consciousness, and how various aspects of phenomenology may in principle be addressed in terms of the geometry of information integration.

Integrated information theory of consciousness: an updated account.

This article presents an updated account of integrated information theory of consciousness (liT) and some of its implications. /IT stems from thought experiments that lead to phenomenological axioms (existence, compositionality, information, integration, exclusion) and corresponding ontological postulates. The information axiom asserts that every experience is spec~fic - it is what it is by differing in its particular way from a large repertoire of alternatives. The integration axiom asserts that each experience is unified- it cannot be reduced to independent components. The exclusion axiom asserts that every experience is definite - it is limited to particular things and not others and flows at a particular speed and resolution. /IT formalizes these intuitions with postulates. The information postulate states that only "differences that make a difference" from the intrinsic perpective of a system matter: a mechanism generates cause-effect information if its present state has selective past causes and selective future effects within a system. The integration postulate states that only information that is irreducible matters: mechanisms generate integrated information only to the extent that the information they generate cannot be partitioned into that generated within independent components. The exclusion postulate states that only maxima of integrated information matter: a mechanism specifies only one maximally irreducible set of past causes and future effects - a concept. A complex is a set of elements specifying a maximally irreducible constellation of concepts, where the maximum is evaluated over elements and at the optimal spatiatemporal scale. Its concepts specify a maximally integrated conceptual information structure or quale, which is identical with an experience. Finally, changes in information integration upon exposure to the environment reflect a system's ability to match the causal structure of the world. After introducing an updated definition of information integration and related quantities, the article presents some theoretical considerations about the relationship between information and causation and about the relational structure of concepts within a qua/e. It also explores the relationship between the temporal grain size of information integration and the dynamic of metastable states in the corticothalamic complex. Finally, it summarizes how liT accounts for empirical findings about the neural substrate of consciousness, and how various aspects of phenomenology may in principle be addressed in terms of the geometry of information integration.

Cortical mechanisms of loss of consciousness: insight from TMS/EEG studies.

In a recent series of experiments we recorded the electroencephalogram (EEG) response to a direct cortical stimulation in humans during wakefulness, NREM sleep, REM sleep and anesthesia by means of a combination of transcranial magnetic stimulation (TMS) and high-density EEG (hd-EEG). TMS/hd-EEG measurements showed that, while during wakefulness and REM sleep the brain is able to sustain long-range specific patterns of activation, during NREM sleep and Midazolam-induced anesthesia, when consciousness fades, this ability is lot: the thalamocortical system, despite being active and reactive, either breaks down in causally independent modules (producing a local slow wave), or it bursts into an explosive and non-specific response (producing a global EEG slow wave). We hypothesize that, like spontaneous sleep slow waves, the slow waves triggered by TMS during sleep and anaesthesia are due to bistability between upand down-states in thalamocortical circuits. In this condition, the inescapable occurrence of a silent, down state after an initial activation impairs the ability of thalamocortical circuits to sustain long-range, differentiated patterns of activation, a theoretical requisite for consciousness. According to animal experiments and computer simulations, thalamocortical bistability may result from increased K-currents, from alterations of the balance between excitation and inhibition and from partial cortical de-afferentation. We hypothesize that these factor may play an important role in determining loss, and recovery, of consciousness also in brain-injured subjects. If this is the case, some types of brain lesions may impair information transmission, above and beyond the associated anatomical disconnection, by inducing bistability in portions of the thalamocortical system that are otherwise healthy.

Information integration: its relevance to brain function and consciousness.

A proper understanding of cognitive functions cannot be achieved without an understanding of consciousness, both at the empirical and at the theoretical level. This paper argues that consciousness has to do with a system's capacity for information integration. In this approach, every causal mechanism capable of choosing among alternatives generates information, and information is integrated to the extent that it is generated by a system above and beyond its parts. The set of integrated informational relationships generated by a complex of mechanisms--its quale--specify both the quantity and the quality of experience. As argued below, depending on the causal structure of a system, information integration can reach a maximum value at a particular spatial and temporal grain size. It is also argued that changes in information integration reflect a system's ability to match the causal structure of the world, both on the input and the output side. After a brief review suggesting that this approach is consistent with several experimental and clinical observations, the paper concludes with some prospective remarks about the relevance of understanding information integration for analyzing cognitive function, both normal and pathological.

Non-fluent aphasia and neural reorganization after speech therapy: insights from human sleep electrophysiology and functional magnetic resonance imaging.

Stroke is associated with long-term functional deficits. Behavioral interventions are often effective in promoting functional recovery and plastic changes. Recent studies in normal subjects have shown that sleep, and particularly slow wave activity (SWA), is tied to local brain plasticity and may be used as a sensitive marker of local cortical reorganization after stroke. In a pilot study, we assessed the local changes induced by a single exposure to a therapeutic session of IMITATE (Intensive Mouth Imitation and Talking for Aphasia Therapeutic Effects), a behavioral therapy used for recovery in patients with post-stroke aphasia. In addition, we measured brain activity changes with functional magnetic resonance imaging (fMRI) in a language observation task before, during and after the full IMITATE rehabilitative program. Speech production improved both after a single exposure and the full therapy program as measured by the Western Aphasia Battery (WAB) Repetition subscale. We found that IMITATE induced reorganization in functionally-connected, speech-relevant areas in the left hemisphere. These preliminary results suggest that sleep hd-EEGs, and the topographical analysis of SWA parameters, are well suited to investigate brain plastic changes underpinning functional recovery in neurological disorders.

Attention modulation regulates both motor and non-motor performance: a high-density EEG study in Parkinson's disease.

We have previously shown that, in early stages of Parkinson's disease (PD), patients with higher reaction times are also more impaired in visual sequence learning, suggesting that movement preparation shares resources with the learning of visuospatial sequences. Here, we ascertained whether, in patients with PD, the pattern of the neural correlates of attentional processes of movement planning predict sequence learning and working memory abilities. High density Electroencephalography (EEG, 256 electrodes) was recorded in 19 patients with PD performing reaching movements in a choice reaction time paradigm. Patients were also tested with Digit Span and performed a visuomotor sequence learning task that has an important declarative learning component. We found that attenuation of alpha/beta oscillatory activity before the stimulus presentation in frontoparietal regions significantly correlated with reaction time in the choice reaction time task, similarly to what we had previously found in normal subjects. In addition, such activity significantly predicted the declarative indices of sequence learning and the scores in the Digit Span task. These findings suggest that some motor and non motor PD signs might have common neural bases, and thus, might have a similar response to the same behavioral therapy. In addition, these results might help in designing and testing the efficacy of novel rehabilitative approaches to improve specific aspects of motor performance in PD and other neurological disorders.

Slow waves, synaptic plasticity and information processing: insights from transcranial magnetic stimulation and high-density EEG experiments.

Sleep slow waves are the main phenomenon underlying NREM sleep. They are homeostatically regulated, they are thought to be linked to learning and plasticity processes and, at the same time, they are associated with marked changes in cortical information processing. Using transcranial magnetic stimulation (TMS) and high-density (hd) EEG we can measure slow waves, induce and measure plastic changes in the cerebral cortex and directly assess corticocortical information transmission. In this manuscript we review the results of recent experiments in which TMS with hd-EEG is used to demonstrate (i) a causal link between cortical plastic changes and sleep slow waves and (ii) a causal link between slow waves and the decreased ability of thalamocortical circuits to integrate information and to generate conscious experience during NREM sleep. The data presented here suggest a unifying mechanism linking slow waves, plasticity and cortical information integration; moreover, they suggest that TMS can be used as a nonpharmacological means to controllably induce slow waves in the human cerebral cortex.

Consciousness and complexity.

Conventional approaches to understanding consciousness are generally concerned with the contribution of specific brain areas or groups of neurons. By contrast, it is considered here what kinds of neural processes can account for key properties of conscious experience. Applying measures of neural integration and complexity, together with an analysis of extensive neurological data, leads to a testable proposal-the dynamic core hypothesis-about the properties of the neural substrate of consciousness.

Neuronal gene expression in the waking state: a role for the locus coeruleus.

Several transcription factors are expressed at higher levels in the waking than in the sleeping brain. In experiments with rats, the locus coeruleus, a noradrenergic nucleus with diffuse projections, was found to regulate such expression. In brain regions depleted of noradrenergic innervation, amounts of c-Fos and nerve growth factor-induced A after waking were as low as after sleep. Phosphorylation of cyclic adenosine monophosphate response element-binding protein was also reduced. In contrast, electroencephalographic activity was unchanged. The reduced activity of locus coeruleus neurons may explain why the induction of certain transcription factors, with potential effects on plasticity and learning, does not occur during sleep.

Correlates of sleep and waking in Drosophila melanogaster.

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

Proteomic profiling of the rat cerebral cortex in sleep and waking.

Transcriptomic studies have shown that hundreds of genes change their expression levels across the sleep/waking cycle, and found that waking-related and sleep-related mRNAs belong to different functional categories. Proteins, however, rather than DNA or RNA, carry out most of the cellular functions, and direct measurements of protein levels and activity are required to assess the effects of behavioral states on the overall functional state of the cell. Here we used surface-enhanced laser desorption-ionization (SELDI), followed by time-of-flight mass spectrometry, to obtain a large-scale profiling of the proteins in the rat cerebral cortex whose expression is affected by sleep, spontaneous waking, short (6 hours) and long (7 days) sleep deprivation. Each of the 94 cortical samples was profiled in duplicate on 4 different ProteinChip Array surfaces using 2 different matrix molecules. Overall, 1055 protein peaks were consistently detected in cortical samples and 15 candidate biomarkers were selected for identification based on significant changes in multiple conditions (conjunction analysis): 8 "sleep" peaks, 4 "waking" peaks, and 4 "long sleep deprivation" peaks. Four candidate biomarkers were purified and positively identified. The 3353 Da candidate sleep marker was identified as the 30 amino acid C-terminal fragment of rat histone H4. This region encompasses the osteogenic growth peptide, but a possible link between sleep and this peptide remains highly speculative. Two peaks associated with short and long sleep deprivation were identified as hemoglobin alpha1/2 and beta, respectively, while another peak associated with long sleep deprivation was identified as cytochrome C. The upregulation of hemoglobins and cytochrome C may be part of a cellular stress response triggered by even short periods of sleep loss.

Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice.

A recent hypothesis suggests that a major function of sleep is to renormalize synaptic changes that occur during wakefulness as a result of learning processes [G. Tononi, C. Cirelli, Sleep and synaptic homeostasis: a hypothesis, Brain Res. Bull. 62 (2003) 143-150; G. Tononi, C. Cirelli, Sleep function and synaptic homeostasis, Sleep Med. Rev. 10 (2006) 49-62]. Specifically, according to this synaptic homeostasis hypothesis, wakefulness results in a net increase in synaptic strength, while sleep is associated with synaptic downscaling. Since synaptic activity accounts for a large fraction of brain energy metabolism, one of the predictions of the hypothesis is that if synaptic weight increases in the course of wakefulness, cerebral metabolic rates should also increase, while the opposite would happen after a period of sleep. In this study we therefore measured brain metabolic rate during wakefulness and determined whether it was affected by the previous sleep-wake history. Three groups of mice in which behavioral states were determined by visual observation were subjected to 6h of sleep deprivation (SD). Group 1 was injected with 2-deoxyglucose (2-DG) 45 min before the end of SD, while Group 2 and Group 3 were injected with 2-DG after an additional period (2-3h) of waking or sleep, respectively. During the 45-min interval between 2-DG injection and sacrifice all mice were kept awake. We found that in mice that slept approximately 2.5h the 2-DG-uptake was globally decreased, on average by 15-20%, compared to the first two groups that were kept awake. On average, Group 2, which stayed awake approximately 2h more than Group 1, showed only a small further increase in 2-DG-uptake relative to Group 1. Moreover, the brain regions in which 2-DG-uptake increased the least when waking was prolonged by approximately 2h showed the most pronounced decrease in DG-uptake after sleep. The data are consistent with the prediction that sleep may reset cerebral metabolic rates to a lower level.

Sleep and the fruit fly.

The function of sleep remains a long-standing mystery in neurobiology. The presence of a sleep-like state has recently been demonstrated in the fruit fly, Drosophila melanogaster, meeting the essential behavioral criteria for sleep and also showing pharmacological and molecular correlates of mammalian sleep. This development opens up the possibility of applying genetic analysis to the identification of key molecular components of sleep. A mutant of monoamine metabolism has already been found to affect the homeostatic regulation of sleep-like behavior in the fly. The record of Drosophila in laying the foundations for subsequent studies in mammals argues in favor of the force of this new approach.

A direct demonstration of cortical LTP in humans: a combined TMS/EEG study.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly being used to promote cortical reorganization, under the assumption that it can induce long-term potentiation (LTP) of neural responses. This assumption is supported by several lines of indirect evidence. For example, rTMS of motor cortex can induce a potentiation of muscle motor evoked potentials that outlasts the stimulation by several minutes. In animal models, a direct demonstration of LTP is typically obtained by high-frequency electrical stimulation coupled with local field recordings of population responses. In this study, we exploited a new approach based on combined rTMS/high-density electroencephalography (hd-EEG) to obtain direct, noninvasive evidence for LTP in humans. Cortical responses to single TMS pulses were measured with hd-EEG before and after applying rTMS to motor cortex (5Hz, 1500 pulses). The results demonstrate that, after rTMS, EEG responses at latencies of 15-55ms were significantly potentiated. A topographic analysis revealed that this potentiation was significant at EEG electrodes located bilaterally over premotor cortex. Thus, these findings provide a direct demonstration in humans of LTP induced by rTMS.

Effects of oral temazepam on slow waves during non-rapid eye movement sleep in healthy young adults: A high-density EEG investigation.

Slow waves are characteristic waveforms that occur during non-rapid eye movement (NREM) sleep that play an integral role in sleep quality and brain plasticity. Benzodiazepines are commonly used medications that alter slow waves, however, their effects may depend on the time of night and measure used to characterize slow waves. Prior investigations have utilized minimal scalp derivations to evaluate the effects of benzodiazepines on slow waves, and thus the topography of changes to slow waves induced by benzodiazepines has yet to be fully elucidated. This study used high-density electroencephalography (hdEEG) to evaluate the effects of oral temazepam on slow wave activity, incidence, and morphology during NREM sleep in 18 healthy adults relative to placebo. Temazepam was associated with significant decreases in slow wave activity and incidence, which were most prominent in the latter portions of the sleep period. However, temazepam was also associated with a decrease in the magnitude of high-amplitude slow waves and their slopes in the first NREM sleep episode, which was most prominent in frontal derivations. These findings suggest that benzodiazepines produce changes in slow waves throughout the night that vary depending on cortical topography and measures used to characterize slow waves. Further research that explores the relationships between benzodiazepine-induced changes to slow waves and the functional effects of these waveforms is indicated.