Odor cueing of declarative memories during sleep enhances coordinated spindles and slow oscillations.

Long-term memories are formed by repeated reactivation of newly encoded information during sleep. This process can be enhanced by using memory-associated reminder cues like sounds and odors. While auditory cueing has been researched extensively, few electrophysiological studies have exploited the various benefits of olfactory cueing. We used high-density electroencephalography in an odor-cueing paradigm that was designed to isolate the neural responses specific to the cueing of declarative memories. We show widespread cueing-induced increases in the duration and rate of sleep spindles. Higher spindle rates were most prominent over centro-parietal areas and largely overlapping with a concurrent increase in the amplitude of slow oscillations (SOs). Interestingly, greater SO amplitudes were linked to a higher likelihood of coupling a spindle and coupled spindles expressed during cueing were more numerous in particular around SO up states. We thus identify temporally and spatially coordinated enhancements of sleep spindles and slow oscillations as a candidate mechanism behind cueing-induced memory processing. Our results further demonstrate the feasibility of studying neural activity patterns linked to such processing using olfactory cueing during sleep.

Protocol for spike-triggered closed-loop auditory stimulation during sleep in patients with epilepsy.

Several epilepsies are characterized by interictal spikes in the electroencephalogram occurring preferentially during sleep. We present a closed-loop auditory stimulation protocol with potential for treating sleep epilepsies. We describe the pre-sleep preparations, sleep recordings, the auditory stimulation, in which tones are triggered upon spike detection, and post-sleep procedures. This protocol has been shown to decrease likelihood and amplitude of subsequent spikes in patients with BECTS (Benign epilepsy with centrotemporal spikes) and can be applied to study non-pharmacological treatments of sleep epilepsies. For complete details on the use and execution of this protocol, please refer to Klinzing et al. (2021).

Auditory stimulation during sleep suppresses spike activity in benign epilepsy with centrotemporal spikes.

Benign epilepsy with centrotemporal spikes (BECTS) is a common form of childhood epilepsy linked to diverse cognitive abnormalities. The electroencephalogram of patients shows focal interictal epileptic spikes, particularly during non-rapid eye movement (NonREM) sleep. Spike formation involves thalamocortical networks, which also contribute to the generation of sleep slow oscillations (SOs) and spindles. Motivated by evidence that SO-spindle activity can be controlled through closed-loop auditory stimulation, here, we show in seven patients that auditory stimulation also reduces spike rates in BECTS. Stimulation during NonREM sleep decreases spike rates, with most robust reductions when tones are presented 1.5 to 3.5 s after spikes. Stimulation further reduces the amplitude of spikes closely following tones. Sleep spindles are negatively correlated with spike rates, suggesting that tone-evoked spindle activity mediates the spike suppression. We hypothesize spindle-related refractoriness in thalamocortical circuits as a potential mechanism. Our results open an avenue for the non-pharmacological treatment of BECTS.

Sleep does not aid the generalisation of binocular disparity-based learning to the other visual hemifield.

Visual perceptual learning refers to long-lasting performance improvements on a visual skill - an ability supported by plastic changes in early visual brain areas. Visual perceptual learning has been shown to be induced by training and to benefit from consolidation during sleep, presumably via the reactivation of learning-associated neuronal firing patterns. However, previous studies have almost exclusively relied on a single paradigm, the texture discrimination task, on which performance improvements may rely on higher-order rather than lower-level perceptual skills. In the present study, we tested whether sleep has beneficial effects on a visual disparity discrimination task. We confirm previous findings in showing that the ability to discriminate different disparities is unaffected by sleep during a 12-hr retention period after training. Importantly, we extend these results by providing evidence against an effect of sleep on the generalisation of improved disparity discrimination across the vertical meridian. By relying on a between-subject design, we further exclude carry-over effects as a possible confound present in previous findings. These data argue against sleep as an important factor in the consolidation of a low-level perceptual skill. This sets important constraints on models of the role of sleep and sleep-associated neural reactivation in the consolidation of non-declarative memories.

Coupling of gamma band activity to sleep spindle oscillations - a combined EEG/MEG study.

Sleep spindles are crucial to memory consolidation. Cortical gamma oscillations (30-100 Hz) are considered to reflect processing of memory in local cortical networks. The temporal and regulatory relationship between spindles and gamma activity might therefore provide clues into how sleep strengthens cortical memory representations. Here, combining EEG with MEG recordings during sleep in healthy humans (n = 12), we investigated the temporal relationships of cortical gamma band activity, always measured by MEG, during fast (12-16 Hz) and slow (8-12 Hz) sleep spindles detected in the EEG or MEG. Time-frequency distributions did not show a consistent coupling of gamma to the spindle oscillation, although activity in the low gamma (30-40 Hz) and neighboring beta range (<30 Hz) was generally increased during spindles. However, more fine-grained analyses of cross-frequency interactions revealed that both low and high gamma power (30-100 Hz) was coupled to the phase of slow and fast EEG spindles, importantly, with this coupling at a fixed phase only for the oscillations within an individual spindle, but with variable phase across spindles. We did not observe any coupling of gamma activity for spindles detected solely in the MEG and not in parallel EEG recordings, raising the possibility that these are more local spindles of different quality. Similar to fast spindle activity, low gamma band power followed a ~0.025 Hz infraslow rhythm during sleep whose frequency, however, was significantly faster than that of spindle activity. Our findings suggest a general function of fast and slow spindles that by spanning larger cortical networks might serve to synchronize gamma band activity occurring in more local but distributed networks. Thereby, spindles might help linking local memory processing between distributed networks.

Reactivation during sleep with incomplete reminder cues rather than complete ones stabilizes long-term memory in humans.

Reactivation by reminder cues labilizes memories during wakefulness, requiring reconsolidation to persist. In contrast, during sleep, cued reactivation seems to directly stabilize memories. In reconsolidation, incomplete reminders are more effective in reactivating memories than complete reminders by inducing a mismatch, i.e. a discrepancy between expected and actual events. Whether mismatch is likewise detected during sleep is unclear. Here we test whether cued reactivation during sleep is more effective for mismatch-inducing incomplete than complete reminders. We first establish that only incomplete but not complete reminders labilize memories during wakefulness. When complete or incomplete reminders are presented during 40-min sleep, both reminders are equally effective in stabilizing memories. However, when extending the retention interval for another 7 hours (following 40-min sleep), only incomplete but not complete reminders stabilize memories, regardless of the extension containing wakefulness or sleep. We propose that, during sleep, only incomplete reminders initiate long-term memory stabilization via mismatch detection.

Binocular disparity-based learning is retinotopically specific and independent of sleep.

Sleep supports the consolidation of recently encoded declarative and procedural memories. An important component of this effect is the repeated reactivation of neuronal ensemble activity elicited during memory encoding. For perceptual learning, however, sleep benefits have only been reported for specific tasks and it is not clear whether sleep targets low-level perceptual, higher-order temporal or attentional aspects of performance. Here, we employed a coarse binocular disparity discrimination task, known to rely on low-level stereoscopic vision. We show that human subjects improve over training and retain the same performance level across a 12-h retention period. Improvements do not generalize to other parts of the visual field and are unaffected by whether the retention period contains sleep or not. These results are compatible with the notion that behavioural improvements in binocular disparity discrimination do not additionally benefit from sleep when compared with the same time spent awake. We hypothesize that this might generalize to other strictly low-level perceptual tasks. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Publisher Correction: Mechanisms of systems memory consolidation during sleep.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mechanisms of systems memory consolidation during sleep.

Long-term memory formation is a major function of sleep. Based on evidence from neurophysiological and behavioral studies mainly in humans and rodents, we consider the formation of long-term memory during sleep as an active systems consolidation process that is embedded in a process of global synaptic downscaling. Repeated neuronal replay of representations originating from the hippocampus during slow-wave sleep leads to a gradual transformation and integration of representations in neocortical networks. We highlight three features of this process: (i) hippocampal replay that, by capturing episodic memory aspects, drives consolidation of both hippocampus-dependent and non-hippocampus-dependent memory; (ii) brain oscillations hallmarking slow-wave and rapid-eye movement sleep that provide mechanisms for regulating both information flow across distant brain networks and local synaptic plasticity; and (iii) qualitative transformations of memories during systems consolidation resulting in abstracted, gist-like representations.

Odor cueing during slow-wave sleep benefits memory independently of low cholinergic tone.

RATIONALE: Sleep-dependent memory consolidation depends on the concerted reactivation of memories in the hippocampo-neocortical system. The communication of reactivated information from the hippocampus to the neocortex is assumed to be enabled by low levels of acetylcholine, particularly during slow-wave sleep (SWS). Recent studies suggest that the reactivation of memories does not only occur spontaneously but can also be externally triggered by re-presenting learning-associated cues during sleep. OBJECTIVES: Here we investigated whether the beneficial effect of cued memory reactivation during sleep depends on similar mechanisms as spontaneous reactivation, and specifically on low cholinergic tone. METHODS: In two experimental nights, healthy volunteers learned a visuo-spatial memory task in the presence of an odor before going to sleep for 40 min. In one night, subjects were presented with the odor again during SWS, whereas in the other night they received an odorless vehicle. In half of the subjects, the availability of acetylcholine during sleep was increased by administering the acetylcholine-esterase inhibitor physostigmine. RESULTS: Contrary to our hypothesis, increased cholinergic tone during sleep did not abolish the beneficial effect of odor cueing: memory performance was better after odor cueing compared to odorless vehicle, independent of physostigmine or placebo administration. CONCLUSIONS: This finding challenges the assumption that odor-cued and spontaneous memory reactivation rely on the same neuropharmacological mechanisms.

Sleep's role in the reconsolidation of declarative memories.

Sleep is known to support the consolidation of newly encoded and initially labile memories. Once consolidated, remote memories can return to a labile state upon reactivation and need to become reconsolidated in order to persist. Here we asked whether sleep also benefits the reconsolidation of remote memories after their reactivation and how reconsolidation during sleep compares to sleep-dependent consolidation processes. In three groups, participants were trained on a visuo-spatial learning task in the presence of a contextual odor. Participants in the 'reconsolidation' group learned the task on day 1. On day 2, they were subjected to a reactivation procedure by presenting the odor cue and a mock recall test in the learning context before a 40-min sleep or wake period. Participants in the 'remote consolidation' group followed the same procedure but did not receive reactivation on day 2. Participants in the 'recent consolidation' group skipped the procedure on day 1 and learned the task immediately before the sleep or wake period. After the sleep or wake interval, memory stability was tested in all subjects. The results show that this short 40-min sleep period significantly facilitated the reconsolidation of reactivated memories, whereas the consolidation of non-reactivated remote memories was less affected and recently encoded memories did not benefit at all. These findings tentatively suggest that sleep has a beneficial effect on the reconsolidation of remote memories, acting at a faster rate than sleep-associated consolidation.

Spindle activity phase-locked to sleep slow oscillations.

The <1Hz slow oscillation (SO) and spindles are hallmarks of mammalian non-rapid eye movement and slow wave sleep. Spindle activity occurring phase-locked to the SO is considered a candidate mediator of memory consolidation during sleep. We used source localization of magnetoencephalographic (MEG) and electroencephalographic (EEG) recordings from 11 sleeping human subjects for an in-depth analysis of the temporal and spatial properties of sleep spindles co-occurring with SOs. Slow oscillations and spindles were identified in the EEG and related to the MEG signal, providing enhanced spatial resolution. In the temporal domain, we confirmed a phase-locking of classical 12-15Hz fast spindle activity to the depolarizing SO up-state and of 9-12Hz slow spindle activity to the up-to-down-state transition of the SO. In the spatial domain, we show a broad spread of spindle activity, with less distinct anterior-posterior separation of fast and slow spindles than commonly seen in the EEG. We further tested a prediction of current memory consolidation models, namely the existence of a spatial bias of SOs over sleep spindles as a mechanism to promote localized neuronal synchronization and plasticity. In contrast to that prediction, a comparison of SOs dominating over the left vs. right hemisphere did not reveal any signs of a concurrent lateralization of spindle activity co-occurring with these SOs. Our data are consistent with the concept of the neocortical SO exerting top-down control over thalamic spindle generation. However, they call into question the notion that SOs locally coordinate spindles and thereby inform spindle-related memory processing.

Deficient fear conditioning in psychopathy as a function of interpersonal and affective disturbances.

The diminished fear reactivity is one of the most valid physiological findings in psychopathy research. In a fear conditioning paradigm, with faces as conditioned stimulus (CS) and electric shock as unconditioned stimulus (US), we investigated a sample of 14 high psychopathic violent offenders. Event related potentials, skin conductance responses (SCR) as well as subjective ratings of the CSs were collected. This study assessed to which extent the different facets of the psychopathy construct contribute to the fear conditioning deficits observed in psychopaths. Participants with high scores on the affective facet subscale of the Psychopathy Checklist-Revised (PCL-R) showed weaker conditioned fear responses and lower N100 amplitudes compared to low scorers. In contrast, high scorers on the affective facet rated the CS+ (paired) more negatively than low scorers regarding the CS- (unpaired). Regarding the P300, high scores on the interpersonal facet were associated with increased amplitudes to the CS+ compared to the CS-, while the opposed pattern was found for the antisocial facet. Both, the initial and terminal contingent negative variation indicated a divergent pattern: participants with pronounced interpersonal deficits, showed increased cortical negativity to the CS+ compared to the CS-, whereas a reversed CS+/CS- differentiation was found in offenders scoring high on the antisocial facet. The present study revealed that deficient fear conditioning in psychopathy was most pronounced in offenders with high scores on the affective facet. Event related potentials suggest that participants with distinct interpersonal deficits showed increased information processing, whereas the antisocial facet was linked to decreased attention and interest to the CS+. These data indicate that an approach to the facets of psychopathy can help to resolve ambiguous findings in psychopathy research and enables a more precise and useful description of this disorder.