The relationship between sleep and appetitive conditioning: A systematic review and meta-analysis.

This systematic review and meta-analysis (PROSPERO registration animal/human studies: CRD42021234793/CRD42021234790) examined the relationship between sleep and appetitive conditioning. Inclusion criteria included: a) appetitive conditioning paradigm; b) measure of conditioning; c) sleep measurement and/or sleep loss; d) human and/etor non-human animal samples; and e) written in English. Searches of seven databases returned 3777 publications. The final sample consisted of 42 studies using primarily animal samples and involving food- and drug-related conditioning tasks. We found sleep loss disrupted appetitive conditioning of food rewards (p < 0.001) but potentiated appetitive conditioning of drug rewards (p < 0.001). Furthermore, sleep loss negatively impacted extinction learning irrespective of the reward type. Post-learning sleep was associated with increases in REM sleep (p = 0.02). Findings suggest sleep loss potentiates the impact of psychoactive substances in a manner likely to produce an increased risk of problematic substance use. In obese/overweight populations, sleep loss may be associated with deficits in the conditioning and extinction of reward-related behaviours. Further research should assess the relationship between sleep and appetitive conditioning in humans.

Diurnal Rhythm Robustness in Individuals With PTSD and Insomnia and The Association With Sleep.

Posttraumatic stress disorder (PTSD) and insomnia are characterized by sleep disturbances and daytime functional impairments. Actigraphy metrics can quantify diurnal rhythms via interdaily stability, intradaily variability, relative amplitude, and sleep regularity. Here, we (a) compared diurnal rhythms in PTSD, insomnia, and healthy control samples using linear mixed modeling; (b) compared inter-individual variability of diurnal rhythms between groups using variance ratio tests; and (c) examined correlations between diurnal rhythms and sleep measures within the clinical samples. Participants (N = 98) wore wrist-activity monitors for one week and completed the Insomnia Severity Index and Pittsburgh Sleep Quality Index. Both clinical samples displayed significantly lower interdaily stability, relative amplitude, and sleep regularity compared with controls. Individuals with PTSD and insomnia did not differ on mean diurnal rhythm metrics. Both clinical samples showed more inter-individual variability in relative amplitude compared with controls, and the individuals with PTSD were distinguished from those with insomnia by greater inter-individual variability in interdaily stability and relative amplitude. Relative amplitude in the clinical samples was positively correlated with objective sleep efficiency and total sleep time. This is the first study to compare individuals with PTSD and insomnia on measures of diurnal rhythms, revealing those with PTSD and insomnia to have less robust and more variable diurnal rhythms compared with controls. Individuals with PTSD differed from those with insomnia in inter-individual variability of diurnal rest-activity stability and amplitude, highlighting this population as particularly heterogenous. Diurnal rhythm robustness might be considered an intervention target in insomnia and PTSD populations.

The impact of sleep loss on performance monitoring and error-monitoring: A systematic review and meta-analysis.

Awareness of performance deficits and errors during sleep loss could be protective against the consequences of sleep deprivation, however, it is unclear whether sleep deprived individuals have insight into their performance. We conducted a systematic review and meta-analysis of the impact of sleep loss (sleep duration <6 h) on monitoring of performance and errors using Embase, MEDLINE, PsycINFO & Cochrane Central. We identified 28 studies, 11 of which were appropriate for meta-analysis. The systematic review indicated limited consensus regarding sleep loss impacts on performance monitoring, due to substantial differences in study methodology. However, participants typically demonstrated more conservative estimates of performance during sleep loss. Error-monitoring literature was more consistent, indicating an impairment in error-monitoring following sleep loss. Meta-analyses supported the findings of the systematic review. In terms of methodology, we found the performance monitoring literature is limited by an overreliance on correlational designs, which are likely confounded by response bias. The error-monitoring literature is limited by very few studies utilising behavioural measures to directly measure error-awareness. Future performance monitoring studies must employ methods which control for confounds such as bias, and error-monitoring studies must incorporate combined behavioural and ERP measures to better understand the impact of sleep loss on error-monitoring.

Manipulation of rapid eye movement sleep via orexin and GABAA receptor modulators differentially affects fear extinction in mice: effect of stable versus disrupted circadian rhythm.

Sleep disruption, and especially rapid eye movement (REM) sleep disruption, is associated with fear inhibition impairment in animals and humans. The REM sleep-fear inhibition relationship raises concern for individuals with posttraumatic stress disorder (PTSD), whose sleep disturbance is commonly treated with hypnotics that disrupt and/or decrease REM sleep, such as benzodiazepines or "Z-drugs." Here, we examined the effects of the Z-drug zolpidem, a gamma-aminobutyric acidA (GABAA) receptor positive allosteric modulator, as well as suvorexant, an orexin receptor antagonist (hypnotics which decrease and increase REM sleep, respectively) in the context of circadian disruption in murine models of fear inhibition-related processes (i.e. fear extinction and safety learning). Adult male C57Bl/6J mice completed fear and safety conditioning before undergoing shifts in the light-dark (LD) cycle or maintaining a consistent LD schedule. Fear extinction and recall of conditioned safety were thereafter tested daily. Immediately prior to the onset of the light phase between testing sessions, mice were treated with zolpidem, suvorexant, or vehicle (methylcellulose). Polysomnographic analyses showed the temporal distribution of REM sleep was misaligned during LD cycle-shifts, while REM sleep duration was preserved. Suvorexant increased REM sleep and improved fear extinction rate, relative to zolpidem, which decreased REM sleep. Survival analysis demonstrated LD shifted mice treated with suvorexant were faster to achieve complete extinction than vehicle and zolpidem-treated mice in the LD shifted condition. By contrast, retention of conditioned safety memory was not influenced by either treatment. This study thus provides preclinical evidence for the potential clinical utility of hypnotics which increase REM sleep for fear extinction after PTSD-relevant sleep disturbance.

Effects of orexin receptor antagonism on human sleep architecture: A systematic review.

Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically evaluated. Thus, we performed a systematic review to assess how these compounds effect sleep architecture in healthy and clinical human samples. Relevant articles were identified via searches of PubMed, Embase, the Cochrane central register of controlled trials, and clinicaltrials. gov. From 1147 retrieved records, 18 satisfied inclusion criteria and formed the basis of this review. Of these, fifteen studies administered dual orexin receptor antagonists (DORA) in a healthy control (five studies) or clinical sample (ten studies). By contrast, three studies administered selective orexin receptor-2 antagonists (2-SORA) in either a healthy control (one study) or clinical sample (two studies). Results reveal DORAs increase total sleep time primarily by promoting REM sleep, without affecting, or even decreasing, non-REM sleep, especially in clinical samples. Therefore, the clinical utility of DORAs may depend on the specific sample being treated. For 2-SORAs, limited evidence available precludes firm conclusions about their influence on human sleep architecture and, thus, further investigation of 2-SORAs is required to define their effects and make comparisons on this basis with DORAs.

Circadian disruption impairs fear extinction and memory of conditioned safety in mice.

Animal models of fear conditioning and fear inhibition are frequently employed in the study of associative learning and commonly derive important human implications. Animal and human studies have demonstrated fear processing abilities are moderated by circadian rhythms, however, the influence of circadian disruption on fear inhibition is not well understood. Here, we examined the effects of circadian disruption on fear inhibition processes (i.e., fear extinction and safety learning) in a pre-clinical model. Adult male C57Bl/6 J mice completed cued fear and safety conditioning in the active phase before undergoing acute shifts in the Light-Dark (LD) cycle. Specifically, the light-phase was advanced by eight-hours across a one-day period (Experiment 1) or a two-day period (Experiment 2), before returning to original timing. Fear and safety recall were assessed over two days following LD shifts. Control groups maintained one LD cycle throughout both experiments. In both experiments, mice allocated to LD shifted groups revealed misaligned patterns of previously circadian locomotor activity. In the second recall session of Experiment 1, LD shifted mice demonstrated reduced retention of conditioned safety memory. However, in Experiment 2, LD shifted mice displayed heightened fear across conditioned fear cues in both recall sessions, therefore demonstrating consistent fear extinction impairment. Moreover, in recall session two, these mice revealed impaired ability to suppress fear during initial presentations of fear and safety cues. Overall, our data suggest maintaining a consistent LD cycle may be crucially important to individuals at high-risk of trauma-exposure and subsequent development of posttraumatic stress disorder.

Sex differences in mouse models of fear inhibition: Fear extinction, safety learning, and fear-safety discrimination.

BACKGROUND AND PURPOSE: Women are overrepresented in post-traumatic stress disorder (PTSD), a mental disorder characterised by ineffective inhibition of fear. The use of male animals dominates preclinical studies, which may contribute to a lack of understanding as to why this disparity exists. Thus, the current study explores sex differences in three mouse models of fear inhibition. EXPERIMENTAL APPROACH: All experiments tested male and female C57Bl/6J mice. Experiment 1 employed two fear conditioning protocols, in which tones were paired with footshocks of differing intensity (moderate or intense). Fear recall and extinction were tested subsequently. In Experiment 2, safety learning was investigated. Tones were explicitly unpaired with footshocks during safety conditioning. Recall of safety learning was tested 24 hr later. Experiment 3 assessed a model of fear-safety discrimination. Cued stimuli were paired or never paired with footshocks during fear and safety conditioning, respectively. Discrimination between stimuli was assessed 24 hr later. KEY RESULTS: In fear extinction, males, compared to females, responded with greater fear in sessions most proximal to conditioning but subsequently showed a more rapid fear extinction over time. Sex differences were not observed during safety learning. During fear-safety discrimination, both males and females discriminated between stimuli; however, males revealed a greater level of freezing to stimuli. CONCLUSION AND IMPLICATIONS: The current study provides evidence that sex differences influence fear but not safety-based behaviour in C57Bl/6J mice. These findings indicate that processing of fear, but not safety, may play a greater role in sex differences observed for PTSD. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD.

Antecedentes: El insomnio es común en los miembros del servicio y está asociado con muchos problemas de salud mental y física. Recientemente, se han utilizado datos longitudinales para evaluar el impacto de las alteraciones del sueño en los resultados de salud mental. Estos estudios han demostrado consistentemente las relaciones entre las alteraciones del sueño y el desarrollo de enfermedades mentales.Objetivo: El presente estudio examinó la relación longitudinal entre el trastorno del sueño y la sintomatología del TEPT en una cohorte de infantes y médicos de Marina desplegados en Irak y Afganistán evaluados antes del despliegue, así como a los 3 y 6 meses posteriores al despliegue. Además, nuestro objetivo fue investigar hasta qué punto estas relaciones son moderadas por la gravedad del estrés de combate, y en qué medida estos hallazgos se replican en una segunda cohorte separada de marinos y médicos de la Marina evaluados con medidas idénticas antes del despliegue y dentro de los 3 meses de regreso.Método: El presente estudio empleó modelos de trayectorias de variables latentes para examinar las relaciones entre la alteración del sueño previa al despliegue y los síntomas de reexperimentación posterior al despliegue. Se llevaron a cabo modelos iniciales de trayectorias de retardo cruzadas en muestras de descubrimiento y replicación para validar las relaciones predictivas hipotéticas. Los modelos de seguimiento de las trayectorias de moderación se llevaron a cabo para incluir el efecto de la gravedad del estrés de combate en estas relaciones.Resultados: Los modelos iniciales de retardo cruzado respaldaron una relación significativa entre la alteración del sueño previa al despliegue y los síntomas futuros de TEPT que se vuelven a experimentar en todos los momentos. Los modelos de moderación iniciales mostraron un efecto moderador pequeño de la gravedad del estrés de combate, aunque la principal relación predictiva entre la alteración del sueño previa al despliegue y los síntomas de TEPT se mantuvo significativa. El efecto moderador no fue significativo en la muestra de replicación.Conclusiones: Los resultados de este estudio respaldan que la alteración del sueño previa al despliegue es un factor de riesgo para el desarrollo de síntomas de TEPT posterior al despliegue. Intervenciones dirigidas a normalizar el sueño pueden ser importantes en cuanto a medidas preventivas para el TEPT.