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.

Examining the Effectiveness of a Digital Media Campaign at Reducing the Duration of Untreated Psychosis in New York State: Results From a Stepped-wedge Randomized Controlled Trial.

BACKGROUND AND HYPOTHESIS: Longer duration of untreated psychosis (DUP) predicts worse outcomes in First Episode Psychosis (FEP). Searching online represents one of the first proactive step toward treatment initiation for many, yet few studies have informed how best to support FEP youth as they engage in early online help-seeking steps to care. STUDY DESIGN: Using a stepped-wedge randomized design, this project evaluated the effectiveness of a digital marketing campaign at reducing DUP and raising rates of referrals to FEP services by proactively targeting and engaging prospective patients and their adult allies online. STUDY RESULTS: Throughout the 18-month campaign, 41 372 individuals visited our website, and 371 advanced to remote clinical assessment (median age = 24.4), including 53 allies and 318 youth. Among those assessed (n = 371), 53 individuals (14.3%) reported symptoms consistent with psychotic spectrum disorders (62.2% female, mean age 20.7 years) including 39 (10.5%) reporting symptoms consistent with either Clinical High Risk (ie, attenuated psychotic symptoms; n = 26) or FEP (n = 13). Among those with either suspected CHR or FEP (n = 39), 20 (51.3%) successfully connected with care. The campaign did not result in significant differences in DUP. CONCLUSION: This study highlights the potential to leverage digital media to help identify and engage youth with early psychosis online. However, despite its potential, online education and professional support alone are not yet sufficient to expedite treatment initiation and reduce DUP.

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 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.

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.

Circadian rhythms in auditory hallucinations and psychosis.

Circadian rhythms are imprinted in all organisms and influence virtually all aspects of physiology and behavior in adaptation to the 24-h day-night cycle. This recognition of a circadian timekeeping system permeating essentially all healthy functioning of body and mind quickly leads to the realization that, in turn, human ailments should be probed for the degree to which they are rooted in or marked by disruptions and dysregulations of circadian clock functions in the human body. In this review, we will focus on psychosis as a key mental illness and foremost one of its cardinal symptoms: auditory hallucinations. We will discuss recent empirical evidence and conceptual advances probing the potential role of circadian disruption in auditory hallucinations. Moreover, a dysbalance in excitation and inhibition within cortical networks, which in turn drive a disinhibition of dopaminergic signaling, will be highlighted as central physiological mechanism. Finally, we will propose two avenues for experimentally intervening on the circadian influences to potentially alleviate hallucinations in psychotic disorders.

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.

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.

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 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.

Digital Strategies to Accelerate Help-Seeking in Youth With Psychiatric Concerns in New York State.

Background: Mental illness in transition age youth is common and treatment initiation is often delayed. Youth overwhelmingly report utilizing the Internet to gather information while psychiatric symptoms emerge, however, most are not yet ready to receive a referral to care, forestalling the established benefit of early intervention. Methods: A digital outreach campaign and interactive online care navigation platform was developed and deployed in New York State on October 22, 2020. The campaign offers live connection to a peer or counselor, a self-assessment mental health quiz, and educational material all designed to promote help-seeking in youth and their allies. Results: Between October 22, 2020 and July 31, 2021, the campaign resulted in 581,981 ad impressions, 16,665 (2.9%) clicks, and 13,717 (2.4%) unique website visitors. A third (4,562, 33.2%) completed the quiz and 793 (0.1%) left contact information. Of those, 173 (21.8%) completed a virtual assessment and 155 (19.5%) resulted in a referral to care. The median age of those referred was 21 years (IQR = 11) and 40% were considered to be from low-income areas. Among quiz completers, youth endorsing symptoms of depression or anxiety were more likely to leave contact information (OR = 2.18, 95% CI [1.39, 3.41] and OR = 1.69, 95% CI [1.31, 2.19], respectively) compared to those not reporting symptoms of depression or anxiety. Youth endorsing symptoms of psychosis were less likely to report a desire to receive a referral to care (OR = 0.58, 95% CI [0.43, 0.80]) compared to those who did not endorse symptoms of psychosis. Conclusion: Self-reported symptomatology impact trajectories to care, even at the earliest stages of help-seeking, while youth and their allies are searching for information online. An online care navigation team could serve as an important resource for individuals with emerging behavioral health concerns and help to guide the transition between online information seeking at baseline to care.

An Intersectional Approach to Ethnoracial Disparities in Pathways to Care Among Individuals With Psychosis in Coordinated Specialty Care.

Importance: Intersecting factors of social position including ethnoracial background may provide meaningful ways to understand disparities in pathways to care for people with a first episode of psychosis. Objective: To examine differences in pathways to care by ethnoracial groups and by empirically derived clusters combining multiple factors of social and clinical context in an ethnoracially diverse multisite early-intervention service program for first-episode psychosis. Design, Setting, and Participants: This cohort study used data collected on individuals with recent-onset psychosis (<2 years) by clinicians with standardized forms from October 2013 to January 2020 from a network of 21 coordinated specialty care (CSC) programs in New York State providing recovery-oriented, evidence-based psychosocial interventions and medications to young people experiencing early psychosis. Exposures: Ethnoracial group and other factors of social position (eg, insurance status, living situation, English fluency, geographic region) intersecting with first-contact experiences (ie, type of first service, referral source, and symptoms at referral). Main Outcomes and Measures: Outcome measures were time from onset to first contact, first contact to CSC, and onset to CSC. Results: The total study sample consists of 1726 individuals aged 16 to 30 years and included 452 women (26%), 1263 men (73%), and 11 (<1%) with another gender enrolled in the network of CSC programs. The total sample consisted of 153 Asian (9%), 599 Black (35%), 454 Latinx (26%), and 417 White individuals (24%). White individuals had a significantly shorter time from onset to first contact (median [IQR], 17 [0-80] days) than Asian (median [IQR], 34 [7-94] days) and Black (median [IQR], 30 [1-108] days) individuals but had the longest period from first contact to CSC (median [IQR], 102.5 [45-258] days). Five distinct clusters of individuals emerged that cut across ethnoracial groups. The more disadvantaged clusters in terms of both social position and first-contact experiences had the longest time from onset to first contact, which were longer than for any single ethnoracial group. Conclusions and Relevance: In this cohort study of individuals with recent-onset psychosis, time-to-treatment outcomes differed by ethnoracial group and by empirically derived clusters combining multiple factors of social and clinical context. The examination of disparities in durations to treatment through an intersectional, ethnoracial lens may improve understanding of the inequities resulting from the various intersecting factors that may compound delays in treatment initiation.

Reducing public stigma toward individuals with psychosis across race and gender: A randomized controlled trial of young adults.

BACKGROUND: Social contact-based interventions effectively reduce stigma toward psychosis. We recently demonstrated the efficacy of a 90-second video intervention in reducing stigma. The current randomized controlled study presents four briefer videos differing in presenter's gender/race, with baseline, postintervention, and 30-day follow-up assessments. The study replicates previous findings and examine whether concordance of presenter's and viewer's race/gender enhanced the anti-stigma effect. METHODS: Using a crowdsourcing platform, we recruited 1993 participants ages 18-35 years to one of four brief video-based interventions (Black/White female, Black/White male presenters) or a nonintervention control condition. In the videos, a young presenter with psychosis humanized their illness through an evocative description of living a meaningful and productive life. RESULTS: Group-by-time ANOVA showed a significant group-by-time interaction for the total score of all five stigma domains: social distance, stereotyping, separateness, social restriction, and perceived recovery. One-way ANOVA showed greater reductions in video intervention groups than control at post-intervention and 30-day follow-up, but no differences between video groups. Matching race/gender did not further reduce stigma. CONCLUSIONS: This randomized controlled study replicated and extended previous research findings, by showing stigma reduction across videos that differ in the presenter's gender and race, thus enhancing generalizability. The videos described the experience of psychosis and reduced stigma, suggesting their potential utility on social media platforms to increase the likelihood of seeking services and ultimately may improve access to care among young individuals with psychosis. Future research should address intersectional stigma experiences by focusing on race/gender and culturally tailoring the narrative.

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.

Predictors of Persistent Symptoms in People in Coordinated Specialty Care Services for Early Psychosis in New York State.

OBJECTIVE: This study aimed to determine the prevalence and predictors of persistent transdiagnostic symptoms in the first year of enrollment in OnTrackNY, a coordinated specialty care (CSC) program for individuals with recent-onset nonaffective psychosis. METHODS: Three groups were defined by using the Mental Illness Research, Education, and Clinical Centers Global Assessment of Functioning symptom subscale: persistently symptomatic, intermittent, and improving to moderate. The authors compared groups on baseline demographic characteristics, family and living situation, clinical measures, and pathways to care. RESULTS: Of 1,129 eligible participants, 12% were persistently symptomatic through follow-up. Being medication nonadherent, being homeless, having a diagnosis of schizophrenia, and having a longer duration between symptom onset and program enrollment were predictive of persistent symptoms during the first year of CSC. CONCLUSIONS: Findings suggest that despite intensive treatment, severe symptoms in young people with psychosis may persist because of economic barriers, treatment delays, and lack of stability.

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.

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.

Reply to Legat, B.; Rocher, L. The Limits of Pairwise Correlation to Model the Joint Entropy. Comment on "Nguyen Thi Thanh et al. Entropy Correlation and Its Impacts on Data Aggregation in a Wireless Sensor Network. Sensors 2018, 18, 3118".

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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.