Sleep and the Balance between Memory and Forgetting.

Slow oscillations and delta waves are neuronal activity rhythms that hallmark sleep, but until now their respective functional roles have been impossible to tease apart. Utilizing a closed-loop optogenetic approach in rats, Kim et al. (2019) dissociated the functions of these two canonical rhythms, showing they support the consolidation and forgetting of memories, respectively.

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.

Cortical hyperarousal in individuals with frequent nightmares.

Nightmares are common among the general population and psychiatric patients and have been associated with signs of nocturnal arousal such as increased heart rate or increased high-frequency electroencephalographic (EEG) activity. However, it is still unclear, whether these characteristics are more of a trait occurring in people with frequent nightmares or rather indicators of the nightmare state. We compared participants with frequent nightmares (NM group; n = 30) and healthy controls (controls; n = 27) who spent 4 nights in the sleep laboratory over the course of 8 weeks. The NM group received six sessions of imagery rehearsal therapy (IRT), the 'gold standard' of cognitive-behavioural therapy for nightmares, between the second and the third night. Sleep architecture and spectral power were compared between groups, and between nights of nightmare occurrence and nights without nightmare occurrence in the NM group. Additionally, changes before and after therapy were recorded. The NM group showed increased beta (16.25-31 Hz) and low gamma (31.25-35 Hz) power during the entire night compared to the controls, but not when comparing nights of nightmare occurrence to those without. Moreover, low gamma activity in rapid eye movement sleep was reduced after therapy in the NM group. Our findings indicate, cortical hyperarousal is more of a trait in people with frequent nightmares within a network of other symptoms, but also malleable by therapy. This is not only a new finding for IRT but could also lead to improved treatment options in the future that directly target high-frequency EEG activity.

Closed-loop auditory stimulation of slow-wave sleep in chronic insomnia: a pilot study.

Insomnia is a prevalent and disabling condition whose treatment is not always effective. This pilot study explores the feasibility and effects of closed-loop auditory stimulation (CLAS) as a potential non-invasive intervention to improve sleep, its subjective quality, and memory consolidation in patients with insomnia. A total of 27 patients with chronic insomnia underwent a crossover, sham-controlled study with 2 nights of either CLAS or sham stimulation. Polysomnography was used to record sleep parameters, while questionnaires and a word-pair memory task were administered to assess subjective sleep quality and memory consolidation. The initial analyses included 17 patients who completed the study, met the inclusion criteria, and received CLAS. From those, 10 (58%) received only a small number of stimuli. In the remaining seven (41%) patients with sufficient CLAS, we evaluated the acute and whole-night effect on sleep. CLAS led to a significant immediate increase in slow oscillation (0.5-1 Hz) amplitude and activity, and reduced delta (1-4 Hz) and sigma/sleep spindle (12-15 Hz) activity during slow-wave sleep across the whole night. All these fundamental sleep rhythms are implicated in sleep-dependent memory consolidation. Yet, CLAS did not change sleep-dependent memory consolidation or sleep macrostructure characteristics, number of arousals, or subjective perception of sleep quality. Results showed CLAS to be feasible in patients with insomnia. However, a high variance in the efficacy of our automated stimulation approach suggests that further research is needed to optimise stimulation protocols to better unlock potential CLAS benefits for sleep structure and subjective sleep quality in such clinical settings.

Proteomic analysis of ceftazidime and meropenem-exposed Pseudomonas aeruginosa ATCC 9027.

BACKGROUND: Pseudomonas aeruginosa is well known for its intrinsic ability to resist a wide range of antibiotics, thus complicates treatment. Thus, understanding the response of the pathogen to antibiotics is important for developing new therapies. In this study, proteomic response of P. aeruginosa to the commonly used anti-pseudomonas antibiotics, ceftazidime (Caz) and meropenem (Mem) was investigated. METHODS: P. aeruginosa ATCC 9027, an antibiotic-susceptible strain, was exposed to sub-MIC values of antibiotics either Caz or Mem for 14 days to obtain E1 strains and then cultured in antibiotic-free environments for 10 days to obtain E2 strains. Proteomes of the initial and E1, E2 strains were identified and comparatively analyzed using isobaric tags for relative and absolute quantitation (iTRAQ) in cooperation with nano LC-MS/MS. Noted up and down-regulated proteins were confirmed with quantitative reverse transcriptase PCR (qRT-PCR). RESULTS: Overall, 1039 and 1041 proteins were identified in Caz and Mem-exposed strains, respectively. Upon antibiotic exposure, there were 7-10% up-regulated (Caz: 71, Mem: 85) and down-regulated (Caz: 106, Mem: 69) proteins (1.5-fold change cut-off). For both Caz and Mem, the DEPs were primarily the ones involved in metabolic process, membrane, virulence, protein synthesis, and antibiotic resistance in which proteins involved in antibiotics resistance tended to be up-regulated while proteins involved in protein synthesis and metabolic process were down-regulated. Noted proteins included beta-lactamase AmpC which was up-regulated and OprD which was down-regulated in both the antibiotic-exposed strains. Besides, biofilm formation related proteins TssC1 and Hcp1 in Caz- exposed strains and the membrane/ periplasmic proteins Azu and PagL in Mem-exposed strains were found significantly down-regulated. qRT-PCR results confirmed the expression change of AmpC, Hcp1 and OprD proteins. CONCLUSION: Exposure of Pseudomonas aeruginosa to sub-MIC values of Caz and Mem resulted in around 10% change in its proteome. Not only proteins with confirmed roles in antibiotic resistance mechanisms changed their expression but also virulence- associated proteins. Both Caz and Mem response involved up-regulation of AmpC and down-regulation of OprD. While TssC1 and Hcp1 were responsible for Caz response, Azu and PagL were more likely involved in Mem response.

Real-time, closed-loop, or open-loop stimulation? Navigating a terminological jungle.

Recent advancements in real-time brain stimulation in the sleep field have led to many exciting findings. However, they have also opened up terminological ambiguities about what constitutes "open-loop", "closed-loop", and "real-time" designs. Here, we address core theoretical aspects of these terms in the hopes of strengthening future research on this topic.

Real-time stimulation during sleep: prior findings, novel developments, and future perspectives.

Real-time brain stimulation is a powerful technique that continues to gain importance in the field of sleep and cognition. In this special issue, we collected 14 articles about real-time stimulation during sleep, including one review, 12 research articles and one letter covering both human and rodent research from various fields. We hope this special issue sparks greater interest and inspires fellow sleep researchers and clinicians to develop new ideas in the exciting topic of real-time stimulation.

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.

No difference between slow oscillation up- and down-state cueing for memory consolidation during sleep.

The beneficial effects of sleep for memory consolidation are assumed to rely on the reactivation of memories in conjunction with the coordinated interplay of sleep rhythms like slow oscillations and spindles. Specifically, slow oscillations are assumed to provide the temporal frame for spindles to occur in the slow oscillations up-states, enabling a redistribution of reactivated information within hippocampal-neocortical networks for long-term storage. Memory reactivation can also be triggered externally by presenting learning-associated cues (like odours or sounds) during sleep, but it is presently unclear whether there is an optimal time-window for the presentation of such cues in relation to the phase of the slow oscillations. In the present within-subject comparison, participants (n = 16) learnt word-pairs visually presented with auditory cues of the first syllable. These syllables were subsequently used for real-time cueing either in the up- or down-state of endogenous slow oscillations. Contrary to our hypothesis, we found differences in memory performance neither between up- and down-state cueing, nor between word-pairs that were cued versus uncued. In the up-state cueing condition, higher amounts of rapid eye movement sleep were associated with better memory for cued contents, whereas higher amounts of slow-wave sleep were associated with better memory for uncued contents. Evoked response analyses revealed signs of cue processing in both conditions. Interestingly, both up- and down-state cueing evoked a similar spindle response with the induced slow oscillations up-state at ~1000 ms post-cue. We speculate that our cueing procedure triggered generalised reactivation processes that facilitated the consolidation of both cued and uncued memories irrespective of the slow oscillation phase.

The impact of China-to-US immigration on structural and cultural determinants of HIV-related stigma: implications for HIV care of Chinese immigrants.

Objectives: Asian Americans have poor HIV-related outcomes, yet culturally salient barriers to care remain unclear, limiting development of targeted interventions for this group. We applied the 'what matters most' theory of stigma to identify structural and cultural factors that shape the nature of stigma before and after immigration from China to the US.Design: Semi-structured interviews were conducted with 16 immigrants to New York from China, recruited from an HIV clinic and community centers. Deductive followed by focal inductive qualitative analyses examined how Chinese cultural values (lian, guanxi, renqing) and structural factors influenced stigma before and after immigration.Results: In China, HIV stigma was felt through the loss of lian (moral status) and limited guanxi (social network) opportunities. A social structure characterized by limited HIV knowledge, discriminatory treatment from healthcare systems, and human rights violations impinged on the ability of people living with HIV to fulfill culturally valued goals. Upon moving to the US, positions of structural vulnerability shifted to enable maintenance of lian and formation of new guanxi, thus ameliorating aspects of stigma.Conclusions: HIV prevention and stigma reduction interventions among Chinese immigrants may be most effective by both addressing structural constraints and facilitating achievement of cultural values through clinical, peer, and group interventions.