Andrea Piarulli

Functional Structure of Spontaneous Sleep Slow Oscillation Activity in Humans

Background During non-rapid eye movement (NREM) sleep synchronous neural oscillations between neural silence (down state) and neural activity (up state) occur. Sleep Slow Oscillations (SSOs) events are their EEG correlates. Each event has an origin site and propagates sweeping the scalp. While recent findings suggest a SSO key role in memory consolidation processes, the structure and the propagation of individual SSO events, as well as their modulation by sleep stages and cortical areas have not been well characterized so far. Methodology/Principal Findings We detected SSO events in EEG recordings and we defined and measured a set of features corresponding to both wave shapes and event propagations. We found that a typical SSO shape has a transition to down state, which is steeper than the following transition from down to up state. We show that during SWS SSOs are larger and more locally synchronized, but less likely to propagate across the cortex, compared to NREM stage 2. Also, the detection number of SSOs as well as their amplitudes and slopes, are greatest in the frontal regions. Although derived from a small sample, this characterization provides a preliminary reference about SSO activity in healthy subjects for 32-channel sleep recordings. Conclusions/Significance This work gives a quantitative picture of spontaneous SSO activity during NREM sleep: we unveil how SSO features are modulated by sleep stage, site of origin and detection location of the waves. Our measures on SSOs shape indicate that, as in animal models, onsets of silent states are more synchronized than those of neural firing. The differences between sleep stages could be related to the reduction of arousal system activity and to the breakdown of functional connectivity. The frontal SSO prevalence could be related to a greater homeostatic need of the heteromodal association cortices.

Early subclinical increase in pulmonary water content in athletes performing sustained heavy exercise at sea level: ultrasound lung comet-tail evidence

Whether prolonged strenuous exercise performed by athletes at sea level can produce interstitial pulmonary edema is under debate. Chest sonography allows to estimate extravascular lung water, creating ultrasound lung comet-tail (ULC) artifacts. The aim of the study was to determine whether pulmonary water content increases in Ironmen (n = 31) during race at sea level and its correlation with cardiopulmonary function and systemic proinflammatory and cardiac biohumoral markers. A multiple factor analysis approach was used to determine the relations between systemic modifications and ULCs by assessing correlations among variables and groups of variables showing significant pre-post changes. All athletes were asymptomatic for cough and dyspnea at rest and after the race. Immediately after the race, a score of more than five comet tail artifacts, the threshold for a significant detection, was present in 23 athletes (74%; 16.3 ± 11.2; P < 0.01 ULC after the race vs. rest) but decreased 12 h after the end of the race (13 athletes; 42%; 6.3 ± 8.0; P < 0.01 vs. soon after the race). Multiple factor analysis showed significant correlations between ULCs and cardiac-related variables and NH(2)-terminal pro-brain natriuretic peptide. Healthy athletes developed subclinical increase in pulmonary water content immediately after an Ironman race at sea level, as shown by the increased number of ULCs related to cardiac changes occurring during exercise. Hemodynamic changes are one of several potential factors contributing to the mechanisms of ULCs.

Disentangling different functional roles of evoked K-complex components: Mapping the sleeping brain while quenching sensory processing

During non-REM sleep the largest EEG response evoked by sensory stimulation is the K-complex (eKC), composed of an initial positive bump (P200) followed by a bistable cortical response: a giant negative deflection (N550) and a large positive one (P900), respectively reflecting down states and up states of < 1 Hz oscillations.Sensory-modality-independent topology of N550 and P900, with maximal detection rate on fronto-central areas, has been consistently reported, suggesting that sensory inputs arise to the cortex avoiding specific primary sensory areas. However, these studies neglected latencies of all KC components as a function of electrode sites.Our aim is to identify, component by component, which topological/dynamical properties of eKCs depend on stimulus modality and which are mainly related to local cortical properties. We measured temporal and morphological features of acoustic, tactile and visual eKCs to disentangle specific sensory excitatory activities from aspecific responses due to local proneness to bistability, measured by means of the N550 descending steepness (synchronization in falling into down state).While confirming the sensory-modality independence of N550 and P900 topology with maximal detection rate in fronto-central areas, four main original results emerge from this study: (i) the topology of P200 latency depends on the sensory modality with earliest waves in the stimulation-related primary sensory areas; (ii) P200 rapidly travels as a cortical excitation; (iii) P200-like excitations when KCs are not evoked are detected over the scalp with significantly smaller amplitudes in fronto-central areas, compared to eKC P200s; and (iv) N550 latency mirrors its mean local steepness which is a function of topological proneness to bistability.From these results we can describe the emergence N550/P900 complex as the interplay between a waxing P200 cortical travel and higher fronto-central proneness to bistability.In conclusion, eKCs exhibit a physiological dichotomy: P200 acts as a traveling cortical excitation whose function is to induce the bistable cortical response (N550/P900), which in turn is crucial for maintaining sleep and unconsciousness.

Likeness-Based Detection of Sleep Slow Oscillations in Normal and Altered Sleep Conditions: Application on Low-Density EEG Recordings

Sleep slow oscillation (SSO) is a common EEG pattern of spontaneous activity during nonrapid eye movement sleep. A new method for detecting SSOs is presented and compared to previous canonical methods. The main result of this research is that for the first time an extensive SSO analysis is applied to clinical EEG montages, based on low-density EEG recordings. The proposed method gives positive indications about its effectiveness also for altered sleep, extending the SSO analysis to extreme cases, and thus, opening a new front for investigating pathophysiological correlates of sleep disorders.

Spectral Parameters Modulation and Source Localization of Blink-Related Alpha and Low-Beta Oscillations Differentiate Minimally Conscious State from Vegetative State/Unresponsive Wakefulness Syndrome

Recently, the cortical source of blink-related delta oscillations (delta BROs) in resting healthy subjects has been localized in the posterior cingulate cortex/precuneus (PCC/PCu), one of the main core-hubs of the default-mode network. This has been interpreted as the electrophysiological signature of the automatic monitoring of the surrounding environment while subjects are immersed in self-reflecting mental activities. Although delta BROs were directly correlated to the degree of consciousness impairment in patients with disorders of consciousness, they failed to differentiate vegetative state/unresponsive wakefulness syndrome (VS/UWS) from minimally conscious state (MCS). In the present study, we have extended the analysis of BROs to frequency bands other than delta in the attempt to find a biological marker that could support the differential diagnosis between VS/UWS and MCS. Four patients with VS/UWS, 5 patients with MCS, and 12 healthy matched controls (CTRL) underwent standard 19-channels EEG recordings during resting conditions. Three-second-lasting EEG epochs centred on each blink instance were submitted to time-frequency analyses in order to extract the normalized Blink-Related Synchronization/Desynchronization (nBRS/BRD) of three bands of interest (low-alpha, high-alpha and low-beta) in the time-window of 50–550 ms after the blink-peak and to estimate the corresponding cortical sources of electrical activity. VS/UWS nBRS/BRD levels of all three bands were lower than those related to both CTRL and MCS, thus enabling the differential diagnosis between MCS and VS/UWS. Furthermore, MCS showed an intermediate signal intensity on PCC/PCu between CTRL and VS/UWS and a higher signal intensity on the left temporo-parieto-occipital junction and inferior occipito-temporal regions when compared to VS/UWS. This peculiar pattern of activation leads us to hypothesize that resting MCS patients have a bottom-up driven activation of the task positive network and thus are tendentially prone to respond to environmental stimuli, even though in an almost unintentional way.

Fragments of wake-like activity frame down-states of sleep slow oscillations in humans: New vistas for studying homeostatic processes during sleep

During NREM sleep cortical activity corresponding to EEG fast rhythms (FRs>10 Hz) is interrupted by fragments of neural stillness (down-states), responsible for the negative peak within sleep slow oscillation (SSO). Researchers still debate whether the down-states spontaneously occur or need an initial overshoot in fluctuating activity. Herein, we studied temporally-isolated SSO in healthy subjects in order to identify two distinct EEG markers defining a putative initial up-state: i) a significant positive deflection and ii) an associated FR increase, before the negative peak. We found a positive bump preceding the down-state, which is detectable already at the cortical SSO origin site, both during N2 and N3. This early positive deflection, concurrent with a broadband activation, is characterized by an increase of sigma activity (12-18 Hz) from N2 to N3, while an opposite trend was observed for sigma activity crowning the up-state following the negative peak. Also, we found: (i) FR activations during up-states up to high gamma frequencies; (ii) depressed sigma activity in after-spindle recovery phase; and (iii) tightly coordinated activities between distinct bands (12-36 Hz, ~70 Hz, ~85 Hz and 105-125 Hz). The correlation between different bands suggested a common mechanism for sigma and gamma, and the pre-down-state activation associated with the initial bump suggested an activity ignition for down-state, whose intensity is dependent on sleep stage. In conclusion, we hypothesize that FR accompanying SSO could mark i) sleep homeostatic processes, such as the regulation/stabilization of sleep, counterbalancing the detrimental effects of continuous inputs from peripheries, and ii) neural mechanisms favoring the storage of information acquired during wakefulness.

Metacognitive beliefs relate specifically to sleep quality in primary insomnia: a pilot study.

OBJECTIVE To identify whether metacognitive aspects are a specific mental pattern of primary insomnia (PI) or an aspecific correlate of sleep alterations. METHODS Sleep quality (Pittsburgh Sleep Quality Index: PSQI), anxiety (Self-rating Anxiety State: SAS), depression (Beck Depression Inventory: BDI) and metacognition (Metacognitions Questionnaire - Insomnia: MCQ-I) were evaluated in 24 PI patients, 13 snorers and 17 healthy controls. Rank-transformed PSQI, BDI, SAS and MCQ-I scores were submitted to one-way analysis of variance with group as a between-factor. PSQI was submitted to three-way analysis of covariance (ANCOVA) with MCQ-I, BDI or SAS as covariate and group as a between-factor. Post-hoc analyses were conducted using pairwise comparisons with Sidak correction. RESULTS As expected, PSQI scores significantly differentiated the three groups, one from another: PI had highest scores followed by snorers and healthy controls. PI subjects had MCQ-I scores significantly higher than those of snorers and healthy controls; no difference between the latter groups was found. The ANCOVA on PSQI with MCQ-I as a covariate abolished the difference in sleep quality between PI and snorers, whereas covarying for BDI or SAS left the differences in sleep quality between the groups unchanged. CONCLUSION These preliminary results lead to two main conclusions: (i) metacognitive aspects are more prominent in PI when compared to snorers and healthy controls; (ii) MCQI shows higher sensitivity in defining PI patients, with respect to PSQI. If these findings are confirmed and expanded by further studies, the development of a specific metacognitive model of primary insomnia may be warranted.

Innovative approach to interpret the variability of biomarkers after ultra-endurance exercise: the multifactorial analysis

AIMS We assessed the inter-relationship that exists between variations of different biochemical and hematological parameters following strenuous endurance exercise in Ironmen by using multiple factor analysis (MFA). MFA was used to estimate the associations among groups of parameters in order to identify concurrent changes in many different biochemical variables. MATERIALS & METHODS In total, 14 Ironman athletes were followed before and early after a race. MFA was applied to the parameters that showed a significant variation after the race, as we previously described in detail. Specifically, MFA standardizes data in each group and calculates the global axes (GAs), which are the linear combination of original parameters that maximize the global data variance. RESULTS MFA identified three global axes (GAs) as significant, explaining approximately 62% of the global data variance. The first GA contained NT-proBNP, IL-1ra, IL-6, IL-8 and the oxidative index. The second and third GAs included calcium, creatinine, potassium, uric acid, hemoglobin, hematocrit and glucose. Analysis of the first two GAs showed that changes in the oxidative index were associated with variations in IL-8 and NT-proBNP. CONCLUSION Among all the variables considered, MFA evidenced a close relationship between variations in oxidative stress, IL-8 and NT-proBNP, which may have a meaning in the mechanisms related to the physiological response after strenuous acute exercise.

Self-organized dynamical complexity in human wakefulness and sleep: different critical brain-activity feedback for conscious and unconscious states.

Criticality reportedly describes brain dynamics. The main critical feature is the presence of scale-free neural avalanches, whose auto-organization is determined by a critical branching ratio of neural-excitation spreading. Other features, directly associated to second-order phase transitions, are: (i) scale-free-network topology of functional connectivity, stemming from suprathreshold pairwise correlations, superimposable, in waking brain activity, with that of ferromagnets at Curie temperature; (ii) temporal long-range memory associated to renewal intermittency driven by abrupt fluctuations in the order parameters, detectable in human brain via spatially distributed phase or amplitude changes in EEG activity. Herein we study intermittent events, extracted from 29 night EEG recordings, including presleep wakefulness and all phases of sleep, where different levels of mentation and consciousness are present. We show that while critical avalanching is unchanged, at least qualitatively, intermittency and functional connectivity, present during conscious phases (wakefulness and REM sleep), break down during both shallow and deep non-REM sleep. We provide a theory for fragmentation-induced intermittency breakdown and suggest that the main difference between conscious and unconscious states resides in the backwards causation, namely on the constraints that the emerging properties at large scale induce to the lower scales. In particular, while in conscious states this backwards causation induces a critical slowing down, preserving spatiotemporal correlations, in dreamless sleep we see a self-organized maintenance of moduli working in parallel. Critical avalanches are still present, and establish transient auto-organization, whose enhanced fluctuations are able to trigger sleep-protecting mechanisms that reinstate parallel activity. The plausible role of critical avalanches in dreamless sleep is to provide a rapid recovery of consciousness, if stimuli are highly arousing.

Cognitive auditory evoked potentials in coma: can you hear me?

This scientific commentary refers to ‘Neural detection of complex sound sequences in the absence of consciousness’, by Tzovara et al. (doi:10.1093/brain/awv041). Event related potentials (ERPs), classically measured by EEG, are the electrophysiological brain responses to a stimulus. Somatosensory and auditory ERPs have been used as a non-invasive tool for assessing brain functions and predicting outcomes in disorders of consciousness and coma (for review see Bruno et al. , 2011). While early ERPs (such as the absence of cortical responses on somatosensory-evoked potentials) predict poor outcomes, cognitive ERPs may be indicative of recovery of consciousness after coma (Vanhaudenhuyse et al. , 2008). Auditory cognitive ERPs permit assessment of residual higher-order processing, such as echoic memory (e.g. using mismatch negativity potentials), acoustic and semantic discrimination (e.g. P3 or P300 evoked potentials), and incongruent language detection (e.g. N400 potentials). Classically, these ERP paradigms are based on the detection of a stimulus in violation of an auditory regularity, composed of two neural events, each characterized at the EEG level by a stereotypical morphology and latency: a mismatch negativity followed by a later complex named P300 further divided into an early (P300a) and a late component (P300b). The mismatch negativity is thought to reflect unconscious processing (Daltrozzo et al. , 2009), whereas the P300b has been linked to consciousness (Bekinschtein et al. , 2009). Neither of these ERP components are specific to auditory stimuli and both can be elicited by other sensory modalities. However, auditory cognitive ERPs have been used most extensively in the field of coma because they are easy to deliver and—in contrast to visual ERPs—can be easily acquired in eyes closed conditions. Given the …