Slow Oscillation Up-state Research Articles

The neurophysiology of closed-loop auditory stimulation in sleep: A magnetoencephalography study.

Closed-loop auditory stimulation (CLAS) is a brain modulation technique in which sounds are timed to enhance or disrupt endogenous neurophysiological events. CLAS of slow oscillation up-states in sleep is becoming a popular tool to study and enhance sleep's functions, as it increases slow oscillations, evokes sleep spindles and enhances memory consolidation of certain tasks. However, few studies have examined the specific neurophysiological mechanisms involved in CLAS, in part because of practical limitations to available tools. To evaluate evidence for possible models of how sound stimulation during brain up-states alters brain activity, we simultaneously recorded electro- and magnetoencephalography in human participants who received auditory stimulation across sleep stages. We conducted a series of analyses that test different models of pathways through which CLAS of slow oscillations may affect widespread neural activity that have been suggested in literature, using spatial information, timing and phase relationships in the source-localized magnetoencephalography data. The results suggest that auditory information reaches ventral frontal lobe areas via non-lemniscal pathways. From there, a slow oscillation is created and propagated. We demonstrate that while the state of excitability of tissue in auditory cortex and frontal ventral regions shows some synchrony with the electroencephalography (EEG)-recorded up-states that are commonly used for CLAS, it is the state of ventral frontal regions that is most critical for slow oscillation generation. Our findings advance models of how CLAS leads to enhancement of slow oscillations, sleep spindles and associated cognitive benefits and offer insight into how the effectiveness of brain stimulation techniques can be improved.

Targeted memory reactivation during sleep influences social bias as a function of slow-oscillation phase and delta power.

To understand how memories are reactivated and consolidated during sleep, experimenters have employed the unobtrusive re-presentation of memory cues from a variety of pre-sleep learning tasks. Using this procedure, known as targeted memory reactivation (TMR), we previously found that reactivation of counter-social-bias training during post-training sleep could selectively enhance training effects in reducing unintentional social biases. Here, we describe re-analyses of electroencephalographic (EEG) data from this previous study to characterize neurophysiological correlates of TMR-induced bias reduction. We found that TMR benefits in bias reduction were associated with (a) the timing of memory-related cue presentation relative to the 0.1-1.5Hz slow-oscillation phase and (b) cue-elicited EEG power within the 1-4Hz delta range. Although cue delivery was at a fixed rate in this study and not contingent on the slow-oscillation phase, cues were found to be clustered in slow-oscillation upstates for those participants with stronger TMR benefits. Similarly, higher cue-elicited delta power 250-1000 ms after cue onset was also linked with larger TMR benefits. These electrophysiological results substantiate the claim that memory reactivation altered social bias in the original study, while also informing neural explanations of these benefits. Future research should consider these sleep physiology parameters in relation to TMR applications and to memory reactivation in general.

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.

Dysfunctional Overnight Memory Consolidation in Patients with Schizophrenia in Comparison to Healthy Controls: Disturbed Slow-Wave Sleep as Contributing Factor?

Introduction: Memory deficiency has been shown in schizophrenia patients, but results on the role of sleep parameters in overnight consolidation of associative verbal memory are still missing. Therefore, the aim of our study was to elucidate underlying processes of impaired sleep-related consolidation of associative word pairs in schizophrenia including standard sleep parameters as well as sleep spindle counts and spectral analysis. Methods: Eighteen stably medicated schizophrenia patients and 24 healthy age-matched controls performed an associative declarative memory task before and after polysomnographic recordings. Part of the participants expected verbal associative memory testing in the morning, while the others did not. Furthermore, participants filled in self-rating questionnaires of schizophrenia-typical experiences (Eppendorf Schizophrenia Inventory [ESI] and Psychotic Symptom Rating Scale). Results: Schizophrenia patients performed worse in verbal declarative memory in the evening as well as in overnight consolidation (morning compared to evening performance). While duration of slow-wave sleep was nearly comparable between groups, schizophrenia patients showed lower sleep spindle count, reduced delta power during slow-wave sleep, and reduced spindle power during the slow oscillation (SO) up-state. In healthy but not in schizophrenia patients, a linear relationship between overnight memory consolidation and slow-wave sleep duration as well as delta power was evident. No significant effect with respect to the expectation of memory retrieval was evident in our data. Additionally, we observed a negative linear relationship between total number of sleep spindles and ESI score in healthy participants. Discussion/Conclusion: As expected, schizophrenia patients showed deficient overnight verbal declarative memory consolidation as compared to healthy controls. Reduced sleep spindles, delta power, and spindle power during the SO up-state may link sleep and memory deficiency in schizophrenia. Additionally, the absence of a linear relationship between sleep-related memory consolidation and slow-wave sleep as well as delta power suggests further functional impairments in schizophrenia. Note that this conclusion is based on observational data. Future studies should investigate if stimulation of delta waves during sleep could improve memory performance and thereby quality of life in schizophrenia.

No benefit of auditory closed-loop stimulation on memory for semantically-incongruent associations

Auditory closed-loop stimulation has gained traction in recent years as a means of enhancing slow oscillatory activity and, consequently, sleep-associated memory consolidation. Previous studies on this topic have primarily focused on the consolidation of semantically-congruent associations. In this study, we investigated the effect of auditory closed-loop stimulation on the overnight retention of semantically-incongruent associations. Twelve healthy males (age: M = 20.06, SD = 2.02 years) participated in two experimental conditions (simulation and sham). In the stimulation condition, clicks were delivered in phase with slow oscillation up-states, whereas in the sham condition no auditory stimuli were applied. Corroborating earlier work, stimulation (vs. sham) enhanced the slow oscillation rhythm, phase-coupled spindle activity and slow oscillation power. However, there was no benefit of stimulation on overnight memory retention. These findings suggest that closed-loop stimulation does not benefit semantically-incongruent associations.

Cortical circuit activity underlying sleep slow oscillations and spindles

Slow oscillations and sleep spindles are hallmarks of the EEG during slow-wave sleep (SWS). Both oscillatory events, especially when co-occurring in the constellation of spindles nesting in the slow oscillation upstate, are considered to support memory formation and underlying synaptic plasticity. The regulatory mechanisms of this function at the circuit level are poorly understood. Here, using two-photon imaging in mice, we relate EEG-recorded slow oscillations and spindles to calcium signals recorded from the soma of cortical putative pyramidal-like (Pyr) cells and neighboring parvalbumin-positive interneurons (PV-Ins) or somatostatin-positive interneurons (SOM-Ins). Pyr calcium activity was increased more than threefold when spindles co-occurred with slow oscillation upstates compared with slow oscillations or spindles occurring in isolation. Independent of whether or not a spindle was nested in the slow oscillation upstate, the slow oscillation downstate was preceded by enhanced calcium signal in SOM-Ins that vanished during the upstate, whereas spindles were associated with strongly increased PV-In calcium activity. Additional wide-field calcium imaging of Pyr cells confirmed the enhanced calcium activity and its widespread topography associated with spindles nested in slow oscillation upstates. In conclusion, when spindles are nested in slow oscillation upstates, maximum Pyr activity appears to concur with strong perisomatic inhibition of Pyr cells via PV-Ins and low dendritic inhibition via SOM-Ins (i.e., conditions that might optimize synaptic plasticity within local cortical circuits).

Insights on auditory closed-loop stimulation targeting sleep spindles in slow oscillation up-states

BackgroundThe consolidation of sleep-dependent memories is mediated by an interplay of cortical slow oscillations (SOs) and thalamo-cortical sleep spindles. Whereas an enhancement of SOs with auditory closed-loop stimulation has been proven highly successful, the feasibility to induce and boost sleep spindles with auditory stimulation remains unknown thus far. New methodHere we tested the possibility to enhance spindle activity during endogenous SOs and thereby to promote memory consolidation. Performing a sleep study in healthy humans, we applied an auditory Spindle stimulation and compared it with an Arrhythmic stimulation and a control condition comprising no stimulation (Sham). ResultsWith Spindle stimulation we were not able to directly entrain endogenous spindle activity during SO up-states. Instead, both Spindle and Arrhythmic stimulation evoked a resonant SO response accompanied by an increase in spindle power phase-locked to the SO up-state. Assessment of overnight retention of declarative word-pairs revealed no difference between all conditions. Comparison with existing methodsOur Spindle stimulation produced oscillatory evoked responses (i.e., increases in SOs and spindle activity during SO up-states) quite similar to those observed after the auditory closed-loop stimulation of SOs in previous studies, lacking however the beneficial effects on memory retention. ConclusionOur findings put the endeavour for a selective enhancement of spindle activity via auditory pathways into perspective and reveal central questions with regard to the stimulation efficacy on both an electrophysiological and a neurobehavioral level.

Intensifying sleep slow oscillations does not improve metabolic control in healthy men

Impaired sleep quality and sleep loss compromise glucose homeostasis and metabolic function, but the mechanisms linking sleep and metabolic health are largely unclear. In order to gain insight into the relevance of specific electrophysiological sleep characteristics for metabolic control, we assessed the acute effect on glucose homeostasis as well as energy intake and expenditure of enhancing slow oscillatory activity, a hallmark of slow-wave sleep, by closed-loop auditory stimulation in healthy men. Twenty-two young, normal-weight men underwent an oral glucose tolerance test (oGTT), indirect calorimetry and the assessment of ad-libitum breakfast intake in the morning after nocturnal sleep with or without auditory stimulation in phase with the ongoing rhythmic occurrence of slow oscillation up-states during 210 min of slow-wave sleep in the first night-half. Stimulation vs. no stimulation strongly increased slow oscillatory activity without changing overall sleep structure, but did not alter fasting or oGTT-stimulated measures of glucose homeostasis. Food intake and energy expenditure were likewise comparable between conditions. Findings indicate that in healthy humans electrophysiological sleep quality is tuned to allow for optimal metabolic control. Future studies should investigate the potential of sleep stage-specific interventions to enhance metabolic control and well-being in patients with metabolic ailments.

Thalamic Spindles Promote Memory Formation during Sleep through Triple Phase-Locking of Cortical, Thalamic, and Hippocampal Rhythms

While the interaction of the cardinal rhythms of non-rapid-eye-movement (NREM) sleep-the thalamo-cortical spindles, hippocampal ripples, and the cortical slow oscillations-is thought to be critical for memory consolidation during sleep, the role spindles play in this interaction is elusive. Combining optogenetics with a closed-loop stimulation approach in mice, we show here that only thalamic spindles induced in-phase with cortical slow oscillation up-states, but not out-of-phase-induced spindles, improve consolidation of hippocampus-dependent memory during sleep. Whereas optogenetically stimulated spindles were as efficient as spontaneous spindles in nesting hippocampal ripples within their excitable troughs, stimulation in-phase with the slow oscillation up-state increased spindle co-occurrence and frontal spindle-ripple co-occurrence, eventually resulting in increased triple coupling of slow oscillation-spindle-ripple events. In-phase optogenetic suppression of thalamic spindles impaired hippocampus-dependent memory. Our results suggest a causal role for thalamic sleep spindles in hippocampus-dependent memory consolidation, conveyed through triple coupling of slow oscillations, spindles, and ripples.

Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat.

Cortical slow oscillations (0.1-1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC. In rodents the medial prefrontal cortex (mPFC) consists of several subregions: anterior cingulate cortex (ACC), prelimbic (PrL), infralimbic (IL), and dorsal peduncular cortices (DP). Although each region has a distinct anatomy and function, it is not known whether slow or fast network oscillations differ between subregions in vivo. We have simultaneously recorded slow and fast network oscillations in all four subregions of the rodent mPFC under urethane anesthesia. Slow oscillations were synchronous between the mPFC subregions, and across the hemispheres, with no consistent amplitude difference between subregions. Delta (2-4 Hz) activity showed only small differences between subregions. However, oscillations in the spindle (6-15 Hz)-, beta (20-30 Hz), gamma (30-80 Hz)-, and high-gamma (80-150 Hz)-frequency bands were consistently larger in the dorsal regions (ACC and PrL) compared with ventral regions (IL and DP). In dorsal regions the peak power of spindle, beta, and gamma activity occurred early after onset of the Up-state. In the ventral regions, especially the DP, the oscillatory power in the spindle-, beta-, and gamma-frequency ranges peaked later in the Up-state. These results suggest variations in fast network oscillations within the mPFC that may reflect the different functions and connectivity of these subregions.NEW & NOTEWORTHY We demonstrate, in the urethane-anesthetized rat, that within the medial prefrontal cortex (mPFC) there are clear subregional differences in the fast network oscillations associated with the slow oscillation Up-state. These differences, particularly between the dorsal and ventral subregions of the mPFC, may reflect the different functions and connectivity of these subregions.

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.

Phase of Spontaneous Slow Oscillations during Sleep Influences Memory-Related Processing of Auditory Cues.

Slow-wave sleep (SWS) is characterized by synchronized neural activity alternating between active upstates and quiet downstates. The slow-oscillation upstates are thought to provide a window of opportunity for memory consolidation, particularly conducive to cortical plasticity. Recent evidence shows that sensory cues associated with previous learning can be delivered subtly during SWS to selectively enhance memory consolidation. Our results demonstrate that this behavioral benefit is predicted by slow-oscillation phase at stimulus presentation time. Cues associated with high versus low forgetting based on analysis of subsequent recall performance were delivered at opposite slow-oscillation phases. These results provide evidence of an optimal slow-oscillation phase for memory consolidation during sleep, supporting the idea that memory processing occurs preferentially during cortical upstates.

EEG-guided transcranial magnetic stimulation reveals rapid shifts in motor cortical excitability during the human sleep slow oscillation.

Evoked cortical responses do not follow a rigid input-output function but are dynamically shaped by intrinsic neural properties at the time of stimulation. Recent research has emphasized the role of oscillatory activity in determining cortical excitability. Here we employed EEG-guided transcranial magnetic stimulation (TMS) during non-rapid eye movement sleep to examine whether the spontaneous <1 Hz neocortical slow oscillation (SO) is associated with corresponding fluctuations of evoked responses. Whereas the SO's alternating phases of global depolarization (up-state) and hyperpolarization (down-state) are clearly associated with fluctuations in spontaneous neuronal excitation, less is known about state-dependent shifts in neocortical excitability. In 12 human volunteers, single-pulse TMS of the primary motor cortical hand area (M1(HAND)) was triggered online by automatic detection of SO up-states and down-states in the EEG. State-dependent changes in cortical excitability were traced by simultaneously recording motor-evoked potentials (MEPs) and TMS-evoked EEG potentials (TEPs). Compared to wakefulness and regardless of SO state, sleep MEPs were smaller and delayed whereas sleep TEPs were fundamentally altered, closely resembling a spontaneous SO. However, both MEPs and TEPs were consistently larger when evoked during SO up-states than during down-states, and amplitudes within each SO state depended on the actual EEG potential at the time and site of stimulation. These results provide first-time evidence for a rapid state-dependent shift in neocortical excitability during a neuronal oscillation in the human brain. We further demonstrate that EEG-guided temporal neuronavigation is a powerful tool to investigate the phase-dependent effects of neuronal oscillations on perception, cognition, and motor control.

The influence of learning on sleep slow oscillations and associated spindles and ripples in humans and rats

The mechanisms underlying off-line consolidation of memory during sleep are elusive. Learning of hippocampus-dependent tasks increases neocortical slow oscillation synchrony, and thalamocortical spindle and hippocampal ripple activity during subsequent non-rapid eye movement sleep. Slow oscillations representing an oscillation between global neocortical states of increased (up-state) and decreased (down-state) neuronal firing temporally group thalamic spindle and hippocampal ripple activity, which both occur preferentially during slow oscillation up-states. Here we examined whether slow oscillations also group learning-induced increases in spindle and ripple activity, thereby providing time-frames of facilitated hippocampus-to-neocortical information transfer underlying the conversion of temporary into long-term memories. Learning (word-pairs in humans, odor-reward associations in rats) increased slow oscillation up-states and, in humans, shaped the timing of down-states. Slow oscillations grouped spindle and rat ripple activity into up-states under basal conditions. Prior learning produced in humans an increase in spindle activity focused on slow oscillation up-states. In rats, learning induced a distinct increase in spindle and ripple activity that was not synchronized to up-states. Event-correlation histograms indicated an increase in spindle activity with the occurrence of ripples. This increase was prolonged after learning, suggesting a direct temporal tuning between ripples and spindles. The lack of a grouping effect of slow oscillations on learning-induced spindles and ripples in rats, together with the less pronounced effects of learning on slow oscillations, presumably reflects a weaker dependence of odor learning on thalamo-neocortical circuitry. Slow oscillations might provide an effective temporal frame for hippocampus-to-neocortical information transfer only when thalamo-neocortical systems are already critically involved during learning.

Pattern-Specific Associative Long-Term Potentiation Induced by a Sleep Spindle-Related Spike Train

Spindles are non-rapid eye movement (non-REM) sleep EEG rhythms (7-14 Hz) that occur independently or in association with slow oscillations (0.6-0.8 Hz). Despite their proposed function in learning and memory, their role in synaptic plasticity is essentially unknown. We studied the ability of a neuronal firing pattern underlying spindles in vivo to induce synaptic plasticity in neocortical pyramidal cells in vitro. A spindle stimulation pattern (SSP) was extracted from a slow oscillation upstate that was recorded in a cat anesthetized with ketamine-xylazine, which is known to induce a sleep-like state. To mimic the recurrence of spindles grouped by the slow oscillation, the SSP was repeated every 1.5 s (0.6 Hz). Whole-cell patch-clamp recordings were obtained from layer V pyramidal cells of rat somatosensory cortex with infrared videomicroscopy, and composite EPSPs were evoked within layers II-III. Trains of EPSPs and action potentials simultaneously triggered by the SSP induced an NMDA receptor-dependent short-term potentiation (STP) and an L-type Ca2+ channel-dependent long-term potentiation (LTP). The number of spindle sequences affected the amount of STP-LTP. In contrast, spindle trains of EPSPs alone led to long-term depression. LTP was not consistently induced by a regular firing pattern, a mirrored SSP, or a randomized SSP; however, a synthetic spindle pattern consisting of repetitive spike bursts at 10 Hz reliably induced STP-LTP. Our results show that spindle-associated spike discharges are efficient in modifying excitatory neocortical synapses according to a Hebbian rule. This is in support of a role for sleep spindles in memory consolidation.