The sleep-circadian interface: A window into mental disorders.

Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep-circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.

'Concept creep' in perceptions of mental illness - an experimental examination of prevalence-induced concept change.

The perception of what constitutes mental illness is influenced by various social and medical developments. Prevalence-induced concept change is a phenomenon where decreasing the prevalence of a category leads people to expand their judgment of that concept. In this study, we tested whether changing the prevalence of statements describing mental illness results in a change in the concept of mental illness. Based on a population survey (n = 1031), we created a validated set of 273 brief statements depicting either clear symptoms of mental illness, clear examples of healthy behaviour, or ambiguous situations. We presented a subset of statements to 138 students, asking them to judge whether each statement represented mental illness, or not. After 96 statements, we reduced the prevalence of clearly mentally ill statements in one group, while the proportion of statements denoting clear mental illness remained the same in the other group. In the group where the proportion of clearly mentally ill statements was reduced during the experiment, a concept change of mental illness evolved: participants were more likely to identify a statement as denoting a mental illness. The results indicate that the perceived prevalence of symptoms of mental illness is important for conceptualizing mental illness and that decreasing prevalence broadens the concept of mental illness. These findings add a novel perspective to current debates around diagnostic thresholds, the treatment-prevalence paradox, the medicalization of emotions, and the focus of anti-stigma campaigns.

Circadian rhythms and disorders of the timing of sleep.

The daily alternation between sleep and wakefulness is one of the most dominant features of our lives and is a manifestation of the intrinsic 24 h rhythmicity underlying almost every aspect of our physiology. Circadian rhythms are generated by networks of molecular oscillators in the brain and peripheral tissues that interact with environmental and behavioural cycles to promote the occurrence of sleep during the environmental night. This alignment is often disturbed, however, by contemporary changes to our living environments, work or social schedules, patterns of light exposure, and biological factors, with consequences not only for sleep timing but also for our physical and mental health. Characterised by undesirable or irregular timing of sleep and wakefulness, in this Series paper we critically examine the existing categories of circadian rhythm sleep-wake disorders and the role of the circadian system in their development. We emphasise how not all disruption to daily rhythms is driven solely by an underlying circadian disturbance, and take a broader, dimensional approach to explore how circadian rhythms and sleep homoeostasis interact with behavioural and environmental factors. Very few high-quality epidemiological and intervention studies exist, and wider recognition and treatment of sleep timing disorders are currently hindered by a scarcity of accessible and objective tools for quantifying sleep and circadian physiology and environmental variables. We therefore assess emerging wearable technology, transcriptomics, and mathematical modelling approaches that promise to accelerate the integration of our knowledge in sleep and circadian science into improved human health.

The temporal dynamics of sleep disturbance and psychopathology in psychosis: a digital sampling study.

BACKGROUND: Sleep disruption is a common precursor to deterioration and relapse in people living with psychotic disorders. Understanding the temporal relationship between sleep and psychopathology is important for identifying and developing interventions which target key variables that contribute to relapse. METHODS: We used a purpose-built digital platform to sample self-reported sleep and psychopathology variables over 1 year, in 36 individuals with schizophrenia. Once-daily measures of sleep duration and sleep quality, and fluctuations in psychopathology (positive and negative affect, cognition and psychotic symptoms) were captured. We examined the temporal relationship between these variables using the Differential Time-Varying Effect (DTVEM) hybrid exploratory-confirmatory model. RESULTS: Poorer sleep quality and shorter sleep duration maximally predicted deterioration in psychosis symptoms over the subsequent 1-8 and 1-12 days, respectively. These relationships were also mediated by negative affect and cognitive symptoms. Psychopathology variables also predicted sleep quality, but not sleep duration, and the effect sizes were smaller and of shorter lag duration. CONCLUSIONS: Reduced sleep duration and poorer sleep quality anticipate the exacerbation of psychotic symptoms by approximately 1-2 weeks, and negative affect and cognitive symptoms mediate this relationship. We also observed a reciprocal relationship that was of shorter duration and smaller magnitude. Sleep disturbance may play a causal role in symptom exacerbation and relapse, and represents an important and tractable target for intervention. It warrants greater attention as an early warning sign of deterioration, and low-burden, user-friendly digital tools may play a role in its early detection.

Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia A successfully managed with rituximab - case report and review of the literature.

BACKGROUND: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. CASE PRESENTATION: We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. CONCLUSIONS: Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells.

Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8(+) T cell activation in situ, but it is unclear whether the liver also supports naive CD4(+) T cell activation. In this study, we show that naive CD4(+) T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4(+) T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome-sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4(+) T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4(+) T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.

Induction intravenous cyclophosphamide followed by maintenance oral immunosuppression in refractory myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) can be refractory to conventional immunotherapy. We report on the efficacy and durability of intravenous (IV) remission-induction cyclophosphamide (CYC) followed by oral immunosuppression in refractory MG. METHODS: We identified 8 patients from our medical records with moderate or severe refractory MG who were treated with 6 cycles of IV CYC (0.75 g/m(2) ) every 4 weeks followed by oral immunosuppression. RESULTS: Six patients improved within 3 months of treatment. Four patients remained in clinical remission (mean follow-up 31 months). Two patients responded partially, and 1 patient relapsed after 11 months. Two patients were non-responders. CYC was well tolerated. Acetylcholine receptor antibody levels remained below pretreatment levels in patients in clinical remission. The leukocyte nadir was lower in CYC responders. CONCLUSIONS: Remission-induction IV CYC followed by oral immunosuppression is a rapid, effective, and durable treatment for refractory MG. Adding a post-CYC immunosuppressant may account for low relapse rates compared with other published series.

Self-harm in people with epilepsy: a retrospective cohort study.

OBJECTIVES: Little is known about self-harm in people with epilepsy, despite suicide being recognized as a leading cause of mortality in this population. This study aimed to investigate the characteristics of self-harm in people with epilepsy, and associated demographic and psychosocial factors. METHODS: Patients presenting to hospital following self-harm between 1994 and 2008 were identified from the Oxford Monitoring System for Self-Harm. Epilepsy diagnosis was confirmed through review of medical records. Demographic features, patient, and self-harm characteristics of 132 people with epilepsy and 9,778 self-harm patients without epilepsy were compared using a regression model, adjusting for age, sex, and repetition. Patients presenting between 1998 and 2008 were followed up for all-cause mortality to the end of 2011. RESULTS: The rate of self-harm per individual with epilepsy was 2.04 (95% confidence interval [CI] 1.85-2.25) times that of the comparison group, and time between first and second self-harm events was shorter (hazard ratio 1.86; 1.46-2.38). People with epilepsy were significantly more likely to use antiepileptic medication in overdose, although overall methods of self-harm were similar in the two groups. No significant differences in suicide intent scores or the proportion of patients who died by suicide were found. Previous outpatient psychiatric treatment, longer duration of unemployment, experience of violence, and housing problems were associated with self-harm in people with epilepsy. SIGNIFICANCE: People with epilepsy who self-harm do so more frequently than other self-harm patients. Clinicians should be aware of this and pay attention to contributory factors as these may enhance risk in this population. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Digital Educational Game "O Jardim do Ferro": A Tool for the Prevention of Iron Deficiency Anemia in Childhood.

Objective: To create and evaluate a digital educational game (DEG) for preschool children for the prevention of iron deficiency and iron deficiency anemia. Methodology: The DEG software was developed by a multidisciplinary team, according to Chandler's methodology, in Engine Unity. The game is a 2D platformer, for Android, with three different phases. A quiz was developed for parents/caregivers about iron absorption and anemia. The quiz content was evaluated by experts. The evaluation of the game was carried out through a questionnaire applied in the school for children from 4 to 6 years of age. Results: For the construction of the game, programming, team planning, art, and soundtrack were necessary. The game was registered at the National Institute of Industrial Property. The quiz was evaluated by 14 experts and all questions had more than 80% agreement. The questionnaire was answered by 32 children with a mean age of 5.0 ± 0.7 years, and ∼70% evaluated the game positively. Thus, the acceptability of the software was favored by most players. Conclusion: The "O Jardim do Ferro" software, from its conception to evaluation, proved to be a promising tool to contribute to food and nutrition education actions, providing opportunities for the construction of knowledge about iron-rich foods for the prevention of iron deficiency and iron deficiency anemia in childhood.

Retinoids for preventing the progression of cervical intra-epithelial neoplasia.

BACKGROUND: Invasive cervical carcinoma is preceded by a precancerous phase, cervical intra-epithelial neoplasia (CIN), which can be detected on cervical smears and confirmed by colposcopy and biopsy. Moderate and severe cases of intra-epithelial neoplasia (CIN2 and CIN3) are treated mainly with surgery to prevent progression to invasive carcinoma. Medical methods of preventing the progression or inducing the regression of CIN are needed. Retinoids are potent modulators of epithelial cell growth and differentiation that may have potential for the treatment of CIN. OBJECTIVES: To ascertain whether retinoids can cause regression or prevent progression of CIN. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Review Group's Specialised Register and Non-Trials Database, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2010), and MEDLINE and EMBASE (July 2010).For the 2013 update, the searches were re-run as follows: CENTRAL, Issue 3, 2013; MEDLINE, April, Week 2, 2013; and EMBASE, Week 16, 2013. SELECTION CRITERIA: Randomized controlled trials (RCTs) and non-RCTs of retinoids for treating CIN in women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data from the trials. Adverse effects information was also collected from the trials. MAIN RESULTS: Five RCTs comparing the efficacy of four different retinoids were identified. Two studies examined the effects on CIN2 and CIN3 of the retinoids N-(4-hydroxyphenyl)retinamide (fenretinide) and 9-cis-retinoic acid (aliretinoin) given orally. Two examined the effect of all-trans-retinoic acid administered topically to the cervix. The fifth study investigated the use of 13-cis-retinoic acid (isotretinoin) given orally to human immunodeficiency virus (HIV)-positive participants with CIN1 and condyloma.Four studies reported no significant effect of retinoids on the progression to higher grades of CIN, and the fifth did not report data on progression. In all studies retinoids had no significant effect on regression of CIN3. Two studies reported that retinoids were associated with regression of CIN2. One reported a greater complete regression of CIN2 over that seen with placebo, which was of borderline statistical significance (odds ratio (OR) 0.5, 95% confidence interval (CI) 0.25 to 1.02). The other study reported a nonsignificant dose-related trend toward increased rates of complete and partial regression compared with placebo. One study reported significantly worse outcomes in women receiving retinoid (OR for regression 6.00, 95% CI 1.00 to 35.91). In general, the retinoid medications were well tolerated.In the 2010 review and in this update, no new studies were identified for inclusion. AUTHORS' CONCLUSIONS: The retinoids studied are not effective in causing regression of CIN3 but may have some effect on CIN2. The data on CIN1 are inadequate. Retinoids are not effective in preventing progression of CIN of any grade. At the doses given for the duration of treatment studied, the retinoids were reasonably well tolerated.

Sleep Abnormalities in Different Clinical Stages of Psychosis: A Systematic Review and Meta-analysis.

Importance: Abnormal sleep is frequent in psychosis; however, sleep abnormalities in different stages (ie, clinical high risk for psychosis [CHR-P], early psychosis [EP], and chronic psychosis [CP]) have not been characterized. Objective: To identify sleep abnormalities across psychosis stages. Data Sources: Web of Science and PubMed were searched between inception and June 15, 2022. Studies written in English were included. Study Selection: Sleep disturbance prevalence studies and case-control studies reporting sleep quality, sleep architecture, or sleep electroencephalography oscillations in CHR-P, EP, or CP. Data Extraction and Synthesis: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Stage-specific and pooled random-effects meta-analyses were conducted, along with the assessment of heterogeneity, study quality, and meta-regressions (clinical stage, sex, age, medication status, and psychotic symptoms). Main Outcomes and Measures: Sleep disturbance prevalence, self-reported sleep quality, sleep architecture (total sleep time, sleep latency, sleep efficiency, nonrapid eye movement, rapid eye movement stages, and number of arousals), and sleep electroencephalography oscillations (spindle density, amplitude, and duration, and slow wave density). Results: Fifty-nine studies with up to 6710 patients (n = 5135 for prevalence) and 977 controls were included. Sleep disturbance prevalence in pooled cases was 50% (95% CI, 40%-61%) and it was similar in each psychosis stage. Sleep quality was worse in pooled cases vs controls (standardized mean difference [SMD], 1.00 [95% CI, 0.70-1.30]). Sleep architecture alterations included higher sleep onset latency (SMD [95% CI]: pooled cases, 0.96 [0.62-1.30]; EP, 0.72 [0.52-0.92]; CP, 1.36 [0.66-2.05]), higher wake after sleep onset (SMD [95% CI]: pooled cases, 0.5 [0.29-0.71]; EP, 0.62 [0.34-0.89]; CP, 0.51 [0.09-0.93]), higher number of arousals (SMD [95% CI]: pooled cases, 0.45 [0.07-0.83]; CP, 0.81 [0.30-1.32]), higher stage 1 sleep (SMD [95% CI]: pooled cases, 0.23 [0.06-0.40]; EP, 0.34 [0.15-0.53]), lower sleep efficiency (SMD [95% CI]: pooled cases, -0.75 [-0.98 to -0.52]; EP, -0.90 [-1.20 to -0.60]; CP, -0.73 [-1.14 to -0.33]), and lower rapid eye movement density (SMD [95% CI]: pooled cases, 0.37 [0.14-0.60]; CP, 0.4 [0.19-0.77]). Spindle parameter deficits included density (SMD [95% CI]: pooled cases, -1.06 [-1.50 to -0.63]; EP, -0.80 [-1.22 to -0.39]; CP, -1.39 [-2.05 to -0.74]; amplitude: pooled cases, -1.08 [-1.33 to -0.82]; EP, -0.86 [-1.24 to -0.47]; CP, -1.25 [-1.58 to -0.91]; and duration: pooled cases: -1.2 [-1.69 to -0.73]; EP, -0.71 [-1.08 to -0.34]; CP, -1.74 [-2.10 to -1.38]). Individuals with CP had more frequent arousals vs CHR-P (z = 2.24, P = .02) and reduced spindle duration vs EP (z = -3.91, P < .001). Conclusions and Relevance: In this systematic review and meta-analysis, sleep disturbances were found to be prevalent throughout the course of psychosis, and different psychosis stages showed both shared and distinct abnormalities in sleep quality, architecture, and spindles. These findings suggest that sleep should become a core clinical target and research domain from at-risk to early and chronic stages of psychosis.

Extracting Circadian and Sleep Parameters from Longitudinal Data in Schizophrenia for the Design of Pragmatic Light Interventions.

Sleep and circadian rhythm dysfunction is prevalent in schizophrenia, is associated with distress and poorer clinical status, yet remains an under-recognized therapeutic target. The development of new therapies requires the identification of the primary drivers of these abnormalities. Understanding of the regulation of sleep-wake timing is now sufficiently advanced for mathematical model-based analyses to identify the relative contribution of endogenous circadian processes, behavioral or environmental influences on sleep-wake disturbance and guide the development of personalized treatments. Here, we have elucidated factors underlying disturbed sleep-wake timing by applying a predictive mathematical model for the interaction of light and the circadian and homeostatic regulation of sleep to actigraphy, light, and melatonin profiles from 20 schizophrenia patients and 21 age-matched healthy unemployed controls, and designed interventions which restored sleep-circadian function. Compared to controls, those with schizophrenia slept longer, had more variable sleep timing, and received significantly fewer hours of bright light (light > 500 lux), which was associated with greater variance in sleep timing. Combining the model with the objective data revealed that non 24-h sleep could be best explained by reduced light exposure rather than differences in intrinsic circadian period. Modeling implied that late sleep offset and non 24-h sleep timing in schizophrenia can be normalized by changes in environmental light-dark profiles, without imposing major lifestyle changes. Aberrant timing and intensity of light exposure patterns are likely causal factors in sleep timing disturbances in schizophrenia. Implementing our new model-data framework in clinical practice could deliver personalized and acceptable light-dark interventions that normalize sleep-wake timing.

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder.

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.

Sleep and Circadian Rhythm Disturbance in Remitted Schizophrenia and Bipolar Disorder: A Systematic Review and Meta-analysis.

BACKGROUND: Sleep and circadian rhythm disturbances in schizophrenia are common, but incompletely characterized. We aimed to describe and compare the magnitude and heterogeneity of sleep-circadian alterations in remitted schizophrenia and compare them with those in interepisode bipolar disorder. METHODS: EMBASE, Medline, and PsycINFO were searched for case-control studies reporting actigraphic parameters in remitted schizophrenia or bipolar disorder. Standardized and absolute mean differences between patients and controls were quantified using Hedges' g, and patient-control differences in variability were quantified using the mean-scaled coefficient of variation ratio (CVR). A wald-type test compared effect sizes between disorders. RESULTS: Thirty studies reporting on 967 patients and 803 controls were included. Compared with controls, both schizophrenia and bipolar groups had significantly longer total sleep time (mean difference [minutes] [95% confidence interval {CI}] = 99.9 [66.8, 133.1] and 31.1 [19.3, 42.9], respectively), time in bed (mean difference = 77.8 [13.7, 142.0] and 50.3 [20.3, 80.3]), but also greater sleep latency (16.5 [6.1, 27.0] and 2.6 [0.5, 4.6]) and reduced motor activity (standardized mean difference [95% CI] = -0.86 [-1.22, -0.51] and -0.75 [-1.20, -0.29]). Effect sizes were significantly greater in schizophrenia compared with the bipolar disorder group for total sleep time, sleep latency, and wake after sleep onset. CVR was significantly elevated in both diagnoses for total sleep time, time in bed, and relative amplitude. CONCLUSIONS: In both disorders, longer overall sleep duration, but also disturbed initiation, continuity, and reduced motor activity were found. Common, modifiable factors may be associated with these sleep-circadian phenotypes and advocate for further development of transdiagnostic interventions that target them.

What are we targeting when we treat autism spectrum disorder? A systematic review of 406 clinical trials.

The number of trials aimed at evaluating treatments for autism spectrum disorder has been increasing progressively. However, it is not clear which outcome measures should be used to assess their efficacy, especially for treatments which target core symptoms. The present review aimed to provide a comprehensive overview regarding the outcome measures used in clinical trials for people with autism spectrum disorder. We systematically searched the Web of KnowledgeSM database between 1980 and 2016 to identify published controlled trials investigating the efficacy of interventions in autism spectrum disorder. We included 406 trials in the final database, from which a total of 327 outcome measures were identified. Only seven scales were used in more than 5% of the studies, among which only three measured core symptoms (Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale, and Social Responsiveness Scale). Of note, 69% of the tools were used in the literature only once. Our systematic review has shown that the evaluation of efficacy in intervention trials for autism spectrum disorder relies on heterogeneous and often non-specific tools for this condition. The fragmentation of tools may significantly hamper the comparisons between studies and thus the discovery of effective treatments for autism spectrum disorder. Greater consensus regarding the choice of these measures should be reached.

Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder.

BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans have not been investigated. METHODS: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli. RESULTS: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and similarly to lorazepam and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli. CONCLUSIONS: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.

Acute oxytocin effects in inferring others' beliefs and social emotions in people at clinical high risk for psychosis.

Social deficits are key hallmarks of the Clinical High Risk for Psychosis (CHR-P) state and of established psychotic disorders, and contribute to impaired social functioning, indicating a potential target for interventions. However, current treatments do not significantly ameliorate social impairments in CHR-P individuals. Given its critical role in social behaviour and cognition, the oxytocinergic (OT) system is a promising target for novel interventions in CHR-P subjects. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using functional magnetic resonance imaging (fMRI) on two occasions, once after 40IU self-administered intranasal OT and once after placebo. A modified version of the Sally-Anne task was used to assess brain activation during inferring others' beliefs and social emotions. The Reading the Mind in the Eyes Test was acquired prior to the first scan to test whether OT effects were moderated by baseline social-emotional abilities. OT did not modulate behavioural performances but reduced activation in the bilateral inferior frontal gyrus compared with placebo while inferring others' social emotions. Furthermore, the relationship between brain activation and task performance after OT administration was moderated by baseline social-emotional abilities. While task accuracy during inferring others' social emotion increased with decreasing activation in the left inferior frontal gyrus in CHR-P individuals with low social-emotional abilities, there was no such relationship in CHR-P individuals with high social-emotional abilities. Our findings may suggest that acute OT administration enhances neural efficiency in the inferior frontal gyrus during inferring others' social emotions in those CHR-P subjects with low baseline social-emotional abilities.

Light therapies to improve sleep in intrinsic circadian rhythm sleep disorders and neuro-psychiatric illness: A systematic review and meta-analysis.

Circadian dysregulation causes sleep disturbance and impacts quality of life and functioning. Some interventions target circadian entrainment through modifying light exposure, but existing reviews of light interventions for sleep improvement include few studies in psychiatric populations. We examined effect of light interventions on sleep quality, duration and timing, and effect moderators. We included controlled studies in intrinsic circadian rhythm disorders (such as advanced or delayed sleep) and in neuropsychiatric disorders with assumed high prevalence of circadian dysregulation (such as affective and psychotic disorders). Articles were identified through database searching: 40 studies reporting 49 relevant intervention comparisons met inclusion criteria. Meta-analysis showed improvements in sleep continuity (ES = -0.23, p = 0.000), self-reported sleep disturbance (ES = -0.32, p = 0.014), and advancement of delayed sleep timing (ES = -0.34, p = 0.010). Although the small number of studies limited meta-regression, evening light avoidance was associated with greater increase in total sleep time. Effects of light on sleep and circadian outcomes have received limited attention in studies in psychiatric disorders, but results were promising in these groups. These findings invite further refinement and testing of light interventions to improve sleep in psychiatric disorders, with improved assessment and specification of problems, and the development and implementation of light schedule interventions for delayed sleep.

Capturing Rest-Activity Profiles in Schizophrenia Using Wearable and Mobile Technologies: Development, Implementation, Feasibility, and Acceptability of a Remote Monitoring Platform.

BACKGROUND: There is growing interest in the potential for wearable and mobile devices to deliver clinically relevant information in real-world contexts. However, there is limited information on their acceptability and barriers to long-term use in people living with psychosis. OBJECTIVE: This study aimed to describe the development, implementation, feasibility, acceptability, and user experiences of the Sleepsight platform, which harnesses consumer wearable devices and smartphones for the passive and unobtrusive capture of sleep and rest-activity profiles in people with schizophrenia living in their homes. METHODS: A total of 15 outpatients with a diagnosis of schizophrenia used a consumer wrist-worn device and smartphone to continuously and remotely gather rest-activity profiles over 2 months. Once-daily sleep and self-rated symptom diaries were also collected via a smartphone app. Adherence with the devices and smartphone app, end-of-study user experiences, and agreement between subjective and objective sleep measures were analyzed. Thresholds for acceptability were set at a wear time or diary response rate of 70% or greater. RESULTS: Overall, 14 out of 15 participants completed the study. In individuals with a mild to moderate symptom severity at baseline (mean total Positive and Negative Syndrome Scale score 58.4 [SD 14.4]), we demonstrated high rates of engagement with the wearable device (all participants meeting acceptability criteria), sleep diary, and symptom diary (93% and 86% meeting criteria, respectively), with negative symptoms being associated with lower diary completion rate. The end-of-study usability and acceptability questionnaire and qualitative analysis identified facilitators and barriers to long-term use, and paranoia with study devices was not a significant barrier to engagement. Comparison between sleep diary and wearable estimated sleep times showed good correspondence (ρ=0.50, P<.001). CONCLUSIONS: Extended use of wearable and mobile technologies are acceptable to people with schizophrenia living in a community setting. In the future, these technologies may allow predictive, objective markers of clinical status, including early markers of impending relapse.