Shaping overnight consolidation via slow-oscillation closed-loop targeted memory reactivation

Sleep constitutes a privileged state for new memories to reactivate and consolidate. Previous work has demonstrated that consolidation can be bolstered experimentally either via delivery of reminder cues (targeted memory reactivation [TMR]) or via noninvasive brain stimulation geared toward enhancing endogenous sleep rhythms. Here, we combined both approaches, controlling the timing of TMR cues with respect to ongoing slow-oscillation (SO) phases. Prior to sleep, participants learned associations between unique words and a set of repeating images (e.g., car) while hearing a prototypical image sound (e.g., engine starting). Memory performance on an immediate test vs. a test the next morning quantified overnight memory consolidation. Importantly, two image sounds were designated as TMR cues, with one cue delivered at SO UP states and the other delivered at SO DOWN states. A novel sound was used as a TMR control condition. Behavioral results revealed a significant reduction of overnight forgetting for words associated with UP-state TMR compared with words associated with DOWN-state TMR. Electrophysiological results showed that UP-state cueing led to enhancement of the ongoing UP state and was followed by greater spindle power than DOWN-state cueing. Moreover, UP-state (and not DOWN-state) cueing led to reinstatement of target image representations. Together, these results unveil the behavioral and mechanistic effects of delivering reminder cues at specific phases of endogenous sleep rhythms and mark an important step for the endeavor to experimentally modulate memories during sleep

Susceptibility to auditory closed-loop stimulation of sleep slow oscillations changes with age

Study Objectives Cortical slow oscillations (SOs) and thalamocortical sleep spindles hallmark slow wave sleep and facilitate memory consolidation, both of which are reduced with age. Experiments utilizing auditory closed-loop stimulation to enhance these oscillations showed great potential in young and older subjects. However, the magnitude of responses has yet to be compared between these age groups. We examined the possibility of enhancing SOs and performance on different memory tasks in a healthy middle-aged population using this stimulation and contrast effects to younger adults. Methods In a within-subject design, 17 subjects (55.7 ± 1.0 years) received auditory stimulation in synchrony with SO up-states, which was compared to a no-stimulation sham condition. Overnight memory consolidation was assessed for declarative word-pairs and procedural finger-tapping skill. Post-sleep encoding capabilities were tested with a picture recognition task. Electrophysiological effects of stimulation were compared to a previous younger cohort (n = 11, 24.2 ± 0.9 years). Results Overnight retention and post-sleep encoding performance of the older cohort revealed no beneficial effect of stimulation, which contrasts with the enhancing effect the same stimulation protocol had in our younger cohort. Auditory stimulation prolonged endogenous SO trains and induced sleep spindles phase-locked to SO up-states in the older population. However, responses were markedly reduced compared to younger subjects. Additionally, the temporal dynamics of stimulation effects on SOs and spindles differed between age groups. Conclusions Our findings suggest that the susceptibility to auditory stimulation during sleep drastically changes with age and reveal the difficulties of translating a functional protocol from younger to older populations

Auditory stimulation in-phase with slow oscillations to enhance overnight memory consolidation in patients with schizophrenia?

Sleep-dependent memory consolidation is disturbed in patients with schizophrenia, who furthermore show reductions in sleep spindles and probably also in delta power during sleep. The memory dysfunction in these patients is one of the strongest markers for worse long-term functional outcome. However, therapeutic interventions to normalise memory functions, e.g., with medication, still do not exist. Against this backdrop, we investigated to what extent a non-invasive approach enhancing sleep with real-time auditory stimulation in-phase with slow oscillations might affect overnight memory consolidation in patients with schizophrenia. To this end, we examined 18 patients with stably medicated schizophrenia in a double-blinded sham-controlled design. Memory performance was assessed by a verbal (word list) and a non-verbal (complex figure) declarative memory task. In comparison to a sham condition without auditory stimuli, we found that in patients with schizophrenia, auditory stimulation evokes an electrophysiological response similar to that in healthy participants leading to an increase in slow wave and temporally coupled sleep spindle activity during stimulation. Despite this finding, patients did not show any beneficial effect on the overnight change in memory performance by stimulation. Although the stimulation in our study did not improve the patient's memory, the electrophysiological response gives hope that auditory stimulation could enable us to provide better treatment for sleep-related detriments in these patients in the future

Examining the optimal timing for closed loop auditory stimulation of slow wave sleep in young and older adults

Study Objectives Closed loop auditory stimulation (CLAS) is a method for enhancing slow oscillations (SOs) through the presentation of auditory clicks during sleep. CLAS boosts SOs amplitude and sleep spindle power, but the optimal timing for click delivery remains unclear. Here, we determine the optimal time to present auditory clicks to maximise the enhancement of SO amplitude and spindle likelihood. Methods We examined the main factors predicting SO amplitude and sleep spindles in a dataset of twenty-one young and seventeen older subjects. The participants received CLAS during slow-wave-sleep in two experimental conditions: sham and auditory stimulation. Post-stimulus SOs and spindles were evaluated according to the click-phase on the SOs and compared between and within conditions. Results We revealed that auditory clicks applied anywhere on the positive portion of the SO increased SO amplitudes and spindle likelihood, although the interval of opportunity was shorter in the older group. For both groups, analyses showed that the optimal timing for click delivery is close to the SO peak phase. Click-phase on the SO wave was the main factor determining the impact of auditory stimulation on spindle likelihood for young subjects, whereas for older participants the temporal lag since the last spindle was a better predictor of spindle likelihood. Conclusions Our data suggest that closed-loop auditory stimulation can more effectively boost SOs during specific phase windows, and these differ between young and older participants. It is possible that this is due to the fluctuation of sensory inputs modulated by the thalamocortical networks during the SO

Closed-loop auditory stimulation of sleep slow oscillations: Basic principles and best practices.

Sleep is essential for our physical and mental well-being. During sleep, despite the paucity of overt behavior, our brain remains active and exhibits a wide range of coupled brain oscillations. In particular slow oscillations are characteristic for sleep, however whether they are directly involved in the functions of sleep, or are mere epiphenomena, is not yet fully understood. To disentangle the causality of these relationships, experiments utilizing techniques to detect and manipulate sleep oscillations in real-time are essential. In this review, we first overview the theoretical principles of closed-loop auditory stimulation (CLAS) as a method to study the role of slow oscillations in the functions of sleep. We then describe technical guidelines and best practices to perform CLAS and analyze results from such experiments. We further provide an overview of how CLAS has been used to investigate the causal role of slow oscillations in various sleep functions. We close by discussing important caveats, open questions, and potential topics for future research

第848回 千葉医学会例会・第7回 磯野外科例会 60.

<p>Shown are membrane voltages of the cortical pyramidal (top) and the thalamic relay population (bottom). During N3 the model shows ongoing slow oscillatory activity. In contrast to sleep stage N2, SOs cannot be identified as isolated events. Furthermore, there are no isolated spindle oscillations and spindle activity is time-locked to SOs. Parameters are given in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005022#pcbi.1005022.t002" target="_blank">Table 2</a>.</p

A Thalamocortical Neural Mass Model of the EEG during NREM Sleep and Its Response to Auditory Stimulation

Few models exist that accurately reproduce the complex rhythms of the thalamocortical system that are apparent in measured scalp EEG and at the same time, are suitable for large-scale simulations of brain activity. Here, we present a neural mass model of the thalamocortical system during natural non-REM sleep, which is able to generate fast sleep spindles (12–15 Hz), slow oscillations (<1 Hz) and K-complexes, as well as their distinct temporal relations, and response to auditory stimuli. We show that with the inclusion of detailed calcium currents, the thalamic neural mass model is able to generate different firing modes, and validate the model with EEG-data from a recent sleep study in humans, where closed-loop auditory stimulation was applied. The model output relates directly to the EEG, which makes it a useful basis to develop new stimulation protocols

Characterization of K-Complexes and Slow Wave Activity in a Neural Mass Model

NREM sleep is characterized by two hallmarks, namely K-complexes (KCs) during sleep stage N2 and cortical slow oscillations (SOs) during sleep stage N3. While the underlying dynamics on the neuronal level is well known and can be easily measured, the resulting behavior on the macroscopic population level remains unclear. On the basis of an extended neural mass model of the cortex, we suggest a new interpretation of the mechanisms responsible for the generation of KCs and SOs. As the cortex transitions from wake to deep sleep, in our model it approaches an oscillatory regime via a Hopf bifurcation. Importantly, there is a canard phenomenon arising from a homoclinic bifurcation, whose orbit determines the shape of large amplitude SOs. A KC corresponds to a single excursion along the homoclinic orbit, while SOs are noise-driven oscillations around a stable focus. The model generates both time series and spectra that strikingly resemble real electroencephalogram data and points out possible differences between the different stages of natural sleep

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead