Olfactory Cues of Naturally Occurring Systemic Inflammation: A Pilot Study of Seasonal Allergy.

INTRODUCTION: In an attempt to avoid contact with infectious individuals, humans likely respond to generalized rather than specific markers of disease. Humans may thus perceive a noninfectious individual as socially less attractive if they look (e.g., have facial discolouration), move (e.g., have a slower walking pace), or sound (e.g., sneeze) sick. This pilot study tested whether humans are averse to the body odour of noninfectious individuals with a low-grade systemic inflammation. METHODS: We collected the axillary body odour of individuals with severe seasonal allergy (N = 14) and healthy controls (N = 10) during and outside the allergy season and measured serum levels of two inflammatory cytokines (tumour necrosis factor-α and interleukin-5). Independent participants (N = 67) then sampled and rated these odours on intensity and pleasantness. RESULTS: While individuals with seasonal allergy had nominally more unpleasant and intense body odours during the allergy season, relative to outside the allergy season and to healthy controls, these effects were not significant. When examining immune markers, the change in perceived pleasantness of an individual's body odour (from out-to-inside pollen season) was significantly related to the change in their interleukin-5 levels but not to tumour necrosis factor-α. DISCUSSION: Our findings tentatively suggest that the human olfactory system could be sensitive to inflammation as present in a noncommunicable condition. Larger replications are required to determine the role of olfaction in the perception of infectious and noninfectious (e.g., chronic diseases) conditions.

Associations between self-reported sleep, overnight memory consolidation, and emotion perception: A large-scale online study in the general population.

Experimental studies suggest that short or disrupted sleep impairs memory consolidation, mood, and perception of emotional stimuli. However, studies have chiefly relied on laboratory-based study designs and small sample sizes. The aim of this fully online and pre-registered study was to investigate the association between sleep and overnight memory consolidation, emotion perception, and affect in a large, self-selected UK sample. A total of 1646 participants (473 completed) took part in an online study, where they completed a declarative (word-pairs) memory task, emotion perception task (valence ratings of images), and rated their affect within 2 h of bed-time. The following morning, participants reported on their state affect, sleep for the previous night, completed a cued recall task for the previously presented word-pairs, rated the valence of previously viewed images, and completed a surprise recognition task. Demographic data and habitual sleep quality and duration (sleep traits) were also recorded. Habitual sleep traits were associated with immediate recall for the word-pairs task, while self-reported sleep parameters for the specific night were not associated with overnight memory consolidation. Neither habitual sleep traits, nor nightly sleep parameters were associated with unpleasantness ratings to negative stimuli or overnight habituation. Habitual poor sleep was associated with less positive and more negative affect, and morning affect was predicted by the specific night's sleep. This study suggests that overnight emotional processing and declarative memory may not be associated with self-reported sleep across individuals. More work is needed to understand how findings from laboratory-based studies extrapolate to real-world samples and contexts.

Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.

Associations between insomnia symptoms and functional connectivity in the UK Biobank cohort (n = 29,423).

An increasing number of studies harness resting-state fMRI functional connectivity analysis to investigate the neurobiological mechanisms of insomnia. The results to date are inconsistent and the detection of minor and widely distributed alterations in functional connectivity requires large sample sizes. The present study investigated associations between insomnia symptoms and resting-state functional connectivity at the whole-brain level in the largest sample to date. This cross-sectional analysis used resting-state imaging data from the UK Biobank, a large scale, population-based biomedical database. The analysis included 29,423 participants (age: 63.1 ± 7.5 years, 54.3% female), comprising 9210 with frequent insomnia symptoms and 20,213 controls without. Linear models were adjusted for relevant clinical, imaging, and socio-demographic variables. The Akaike information criterion was used for model selection. Multiple comparisons were corrected using the false discovery rate with a significance level of q < 0.05. Frequent insomnia symptoms were associated with increased connectivity within the default mode network and frontoparietal network, increased negative connectivity between the default mode network and the frontoparietal network, and decreased connectivity between the salience network and a node of the default mode network. Furthermore, frequent insomnia symptoms were associated with altered functional connectivity between nodes comprising sensory areas and the cerebellum. These functional alterations of brain networks may underlie dysfunctional affective and cognitive processing in insomnia and contribute to subjectively and objectively impaired sleep. However, it must be noted that the item that was used to assess frequent insomnia symptoms in this study did not assess all the characteristics of clinically diagnosed insomnia.

The effect of sleep continuity disruption on multimodal emotion processing and regulation: a laboratory-based, randomised, controlled experiment in good sleepers.

Previous research shows that experimental sleep deprivation alters emotion processing, suggesting a potential mechanism linking sleep disruption to mental ill-health. Extending previous work, we experimentally disrupted sleep continuity in good sleepers and assessed next-day emotion processing and regulation using tasks with established sensitivity to depression. In a laboratory-based study, 51 good sleepers (37 female; mean [SD] age 24 [3.63] years), were randomised to 1 night of uninterrupted sleep (n = 24) or sleep continuity disruption (n = 27). We assessed emotion perception, attention, and memory the following day. Participants also completed an emotion regulation task and measures of self-reported affect, anxiety, sleepiness, overnight declarative memory consolidation, and psychomotor vigilance. Confirming the effects of the manipulation, sleep continuity disruption led to a marked decrease in polysomnography-defined total sleep time (229.98 versus 434.57 min), increased wake-time after sleep onset (260.66 versus 23.84 min), and increased sleepiness (d = 0.81). Sleep continuity disruption led to increased anxiety (d = 0.68), decreased positive affect (d = -0.62), reduced overnight declarative memory consolidation (d = -1.08), and reduced psychomotor vigilance (longer reaction times [d = 0.64] and more lapses [d = 0.74]), relative to control. However, contrary to our hypotheses, experimental sleep disruption had no effect on perception of, or bias for, emotional facial expressions, emotional memory for words, or emotion regulation following worry induction. In conclusion, 1 night of sleep continuity disruption had no appreciable effect on objective measures of emotion processing or emotion regulation in response to worry induction, despite clear effects on memory consolidation, vigilance, and self-reported affect and anxiety.

Associations Between Sleep Health and Amygdala Reactivity to Negative Facial Expressions in the UK Biobank Cohort.

BACKGROUND: Sleep health (SH) is considered a key determinant of human physiological and psychological well-being. In line with this, previous studies have found that poor sleep is associated with various psychiatric disorders, in particular, with anxiety and depression. Although little is known about the neural mechanisms underlying these associations, recent findings suggest that essential dimensions of SH are associated with altered amygdala reactivity (AR); however, evidence to date is inconsistent and reliant on small sample sizes. METHODS: To address this problem, the current preregistered study investigated associations between SH and AR to negative facial expressions in the UK Biobank cohort (25,758 participants). Drawing on a large sample size and consistent data acquisition, 5 dimensions of SH (insomnia symptoms, sleep duration, daytime sleepiness, chronotype, and sleep medication) were examined. RESULTS: Exploratory analyses revealed that short sleep duration was associated with decreased AR. The remaining SH dimensions and a composite measure of all SH dimensions were not associated with AR. CONCLUSIONS: To our knowledge, this is the largest study to test associations between SH and AR. Habitual short sleep duration may be associated with decreased AR, possibly indicating compensation for impaired prefrontal processes and hampered emotion regulation.

Spontaneous eye movements during eyes-open rest reduce resting-state-network modularity by increasing visual-sensorimotor connectivity.

During wakeful rest, individuals make small eye movements during fixation. We examined how these endogenously driven oculomotor patterns impact topography and topology of functional brain networks. We used a dataset consisting of eyes-open resting-state (RS) fMRI data with simultaneous eye tracking. The eye-tracking data indicated minor movements during rest, which correlated modestly with RS BOLD data. However, eye-tracking data correlated well with echo-planar imaging time series sampled from the area of the eye-orbit (EO-EPI), which is a signal previously used to identify eye movements during exogenous saccades and movie viewing. Further analyses showed that EO-EPI data were correlated with activity in an extensive motor and sensorimotor network, including components of the dorsal attention network and the frontal eye fields. Partialling out variance related to EO-EPI from RS data reduced connectivity, primarily between sensorimotor and visual areas. It also produced networks with higher modularity, lower mean connectivity strength, and lower mean clustering coefficient. Our results highlight new aspects of endogenous eye movement control during wakeful rest. They show that oculomotor-related contributions form an important component of RS network topology, and that those should be considered in interpreting differences in network structure between populations or as a function of different experimental conditions.

Objective and Subjective Sleep in Rheumatoid Arthritis and Severe Seasonal Allergy: Preliminary Assessments of the Role of Sickness, Central and Peripheral Inflammation.

INTRODUCTION: Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods. AIM: The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness. METHODS: In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion. RESULTS: Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA. CONCLUSION: This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups.

A continuum hypothesis of psychotomimetic rapid antidepressants.

Ketamine, classical psychedelics and sleep deprivation are associated with rapid effects on depression. Interestingly, these interventions also have common psychotomimetic actions, mirroring aspects of psychosis such as an altered sense of self, perceptual distortions and distorted thinking. This raises the question whether these interventions might be acute antidepressants through the same mechanisms that underlie some of their psychotomimetic effects. That is, perhaps some symptoms of depression can be understood as occupying the opposite end of a spectrum where elements of psychosis can be found on the other side. This review aims at reviewing the evidence underlying a proposed continuum hypothesis of psychotomimetic rapid antidepressants, suggesting that a range of psychotomimetic interventions are also acute antidepressants as well as trying to explain these common features in a hierarchical predictive coding framework, where we hypothesise that these interventions share a common mechanism by increasing the flexibility of prior expectations. Neurobiological mechanisms at play and the role of different neuromodulatory systems affected by these interventions and their role in controlling the precision of prior expectations and new sensory evidence will be reviewed. The proposed hypothesis will also be discussed in relation to other existing theories of antidepressants. We also suggest a number of novel experiments to test the hypothesis and highlight research areas that could provide further insights, in the hope to better understand the acute antidepressant properties of these interventions.

Oxazepam and cognitive reappraisal: A randomised experiment.

BACKGROUND: Cognitive reappraisal is a strategy for emotional regulation, important in the context of anxiety disorders. It is not known whether anxiolytic effects of benzodiazepines affect cognitive reappraisal. AIMS: We aimed to investigate the effect of 25 mg oxazepam on cognitive reappraisal. METHODS: In a preliminary investigation, 33 healthy male volunteers were randomised to oxazepam or placebo, and then underwent an experiment where they were asked to use cognitive reappraisal to upregulate or downregulate their emotional response to images with negative or neutral emotional valence. We recorded unpleasantness ratings, skin conductance, superciliary corrugator muscle activity, and heart rate. Participants completed rating scales measuring empathy (Interpersonal Reactivity Index, IRI), anxiety (State-Trait Anxiety Inventory, STAI), alexithymia (Toronto Alexithymia Scale-20, TAS-20), and psychopathy (Psychopathy Personality Inventory-Revised, PPI-R). RESULTS: Upregulation to negative-valence images in the cognitive reappraisal task caused increased unpleasantness ratings, corrugator activity, and heart rate compared to downregulation. Upregulation to both negative- and neutral-valence images caused increased skin conductance responses. Oxazepam caused lower unpleasantness ratings to negative-valence stimuli, but did not interact with reappraisal instruction on any outcome. Self-rated trait empathy was associated with stronger responses to negative-valence stimuli, whereas self-rated psychopathic traits were associated with weaker responses to negative-valence stimuli. CONCLUSIONS: While 25 mg oxazepam caused lower unpleasantness ratings in response to negative-valence images, we did not observe an effect of 25 mg oxazepam on cognitive reappraisal.

A combined fMRI and EMG study of emotional contagion following partial sleep deprivation in young and older humans.

Sleep deprivation is proposed to inhibit top-down-control in emotion processing, but it is unclear whether sleep deprivation affects emotional mimicry and contagion. Here, we aimed to investigate effects of partial sleep deprivation on emotional contagion and mimicry in young and older humans. Participants underwent partial sleep deprivation (3 h sleep opportunity at the end of night), crossed-over with a full sleep condition in a balanced order, followed by a functional magnetic resonance imaging and electromyography (EMG) experiment with viewing of emotional and neutral faces and ratings of emotional responses. The final sample for main analyses was n = 69 (n = 36 aged 20-30 years, n = 33 aged 65-75 years). Partial sleep deprivation caused decreased activation in fusiform gyri for angry faces and decreased ratings of happiness for all stimuli, but no significant effect on the amygdala. Older participants reported more anger compared to younger participants, but no age differences were seen in brain responses to emotional faces or sensitivity to partial sleep deprivation. No effect of the sleep manipulation was seen on EMG. In conclusion, emotional contagion, but not mimicry, was affected by sleep deprivation. Our results are consistent with the previously reported increased negativity bias after insufficient sleep.The Stockholm sleepy brain study: effects of sleep deprivation on cognitive and emotional processing in young and old. https://clinicaltrials.gov/ct2/show/NCT02000076 .

Affect and Arousal in Insomnia: Through a Lens of Neuroimaging Studies.

PURPOSE OF REVIEW: Previous research has struggled with identifying clear-cut, objective counterparts to subjective distress in insomnia. Approaching this discrepancy with a focus on hyperarousal and dysfunctional affective processes, studies examining brain structures and neural networks involved in affect and arousal are reviewed and conclusions for an updated understanding of insomnia are drawn. RECENT FINDINGS: Recent studies found that amygdala reactivity, morphometry and adaptation in insomnia are altered, indicating that processing of negative stimuli is intensified and more lasting. Also, patients with insomnia show aberrant connectivity in the default mode network (DMN) and the salience network (SN), which is associated with subjective sleep disturbances, hyperarousal, maladaptive emotion regulation and disturbed integration of emotional states. The limbic circuit is assumed to play a crucial role in enhanced recall of negative experiences. There is reason to consider insomnia as a disorder of affect and arousal. Dysregulation of the limbic circuit might perpetuate impaired connectivity in the DMN and the SN. However, the interplay between the networks is yet to be researched.

Gray Matter Volume Correlates of Sleepiness: A Voxel-Based Morphometry Study in Younger and Older Adults.

BACKGROUND: Subjectively experienced sleepiness is a problem in society, possibly linked with gray matter (GM) volume. Given a different sleep pattern, aging may affect such associations, possibly due to shrinking brain volume. PURPOSE: The purpose of the present study was to investigate the association between subjectively rated sleepiness and GM volume in thalamus, insula, hippocampus, and orbitofrontal cortex of young and older adults, after a normal night's sleep. METHODS: Eighty-four healthy individuals participated (46 aged 20-30 years, and 38 aged 65-75 years). Morphological brain data were collected in a 3T magnetic resonance imaging (MRI) scanner. Sleepiness was rated multiple times during the imaging sessions. RESULTS: In older, relative to younger, adults, clusters within bilateral mid-anterior insular cortex and right thalamus were negatively associated with sleepiness. Adjustment for the immediately preceding total sleep time eliminated the significant associations. CONCLUSION: Self-rated momentary sleepiness in a monotonous situation appears to be negatively associated with GM volume in clusters within both thalamus and insula in older individuals, and total sleep time seems to play a role in this association. Possibly, this suggests that larger GM volume in these clusters may be protective against sleepiness in older individuals. This notion needs confirmation in further studies.

Sleep restriction caused impaired emotional regulation without detectable brain activation changes-a functional magnetic resonance imaging study.

Sleep restriction has been proposed to cause impaired emotional processing and emotional regulation by inhibiting top-down control from prefrontal cortex to amygdala. Intentional emotional regulation after sleep restriction has, however, never been studied using brain imaging. We aimed here to investigate the effect of partial sleep restriction on emotional regulation through cognitive reappraisal. Forty-seven young (age 20-30) and 33 older (age 65-75) participants (38/23 with complete data and successful sleep intervention) performed a cognitive reappraisal task during fMRI after a night of normal sleep and after restricted sleep (3 h). Emotional downregulation was associated with significantly increased activity in the dorsolateral prefrontal cortex (p FWE < 0.05) and lateral orbital cortex (p FWE < 0.05) in young, but not in older subjects. Sleep restriction was associated with a decrease in self-reported regulation success to negative stimuli (p < 0.01) and a trend towards perceiving all stimuli as less negative (p = 0.07) in young participants. No effects of sleep restriction on brain activity nor connectivity were found in either age group. In conclusion, our data do not support the idea of a prefrontal-amygdala disconnect after sleep restriction, and neural mechanisms underlying behavioural effects on emotional regulation after insufficient sleep require further investigation.

Mood impairment is stronger in young than in older adults after sleep deprivation.

Sleep deprivation commonly impairs affective regulation and causes worse mood. However, the majority of previous research concerns young adults. Because susceptibility to sleep deprivation and emotion regulation change distinctively across adult age, we tested here the hypothesis that the effect of sleep deprivation on mood is stronger in young than in older adults. In an experimental design, young (18-30 years) and older adults (60-72 years) participated in either a sleep control (young, n = 63; older, n = 47) or a total sleep deprivation condition (young, n = 61; older, n = 47). Sleepiness, mood and common symptoms of sleep deprivation were measured using established questionnaires and ratings. Sleep-deprived participants felt more sleepy, stressed and cold, and reported lower vigour and positive affect, regardless of age. All the other outcome measures (negative affect, depression, confusion, tension, anger, fatigue, total mood disturbance, hunger, cognitive attenuation, irritability) showed a weaker response to sleep deprivation in the older group, as indicated by age*sleep deprivation interactions (ps < 0.05). The results show that older adults are emotionally less affected by sleep deprivation than young adults. This tolerance was mainly related to an attenuated increase in negative mood. This could possibly be related to the well-known positivity effect, which suggests that older adults prioritize regulating their emotions to optimize well-being. The results also highlight that caution is warranted when generalizing results from sleep deprivation studies across the adult lifespan.

Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [11C]PBR28 PET study.

Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [11C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.

Effects of late-night short-sleep on in-home polysomnography: relation to adult age and sex.

Bedtime is frequently delayed by many factors in life, and a homeostatic response to the delay may compensate partly for increased time awake and shortened sleep. Because sleep becomes shorter with age and women complain of disturbed sleep more often than men, age and sex differences in the homeostatic response to a delayed bedtime may modify the homeostatic response. The purpose of the present study was to investigate the effect of late-night short-sleep (3 h with awakening at about 07:00 hours) on in-home recorded sleep in men and women in two age groups (20-30 and 65-75 years). Results (N = 59) showed that late-night short-sleep was associated with an increase in percentage of N3 sleep and a decrease in percentage of rapid eye movement sleep, as well as decreases in several measures of sleep discontinuity and rapid eye movement density. Men showed a smaller decrease in percentage of rapid eye movement sleep than women in response to late-night short-sleep, as did older individuals of both sexes compared with younger. Older men showed a weaker percentage of N3 sleep in response to late-night short-sleep than younger men. In general, men showed a greater percentage of rapid eye movement sleep and a lower percentage of N3 sleep than women, and older individuals showed a lower percentage of N3 sleep than younger. In particular, older men showed very low levels of percentage of N3 sleep. We conclude that older males show less of a homeostatic response to late-night short-sleep. This may be an indication of impaired capacity for recovery in older men. Future studies should investigate if this pattern can be linked to gender-associated differences in morbidity and mortality.

The effect of sleep restriction on empathy for pain: An fMRI study in younger and older adults.

Age and sleep both affect emotional functioning. Since sleep patterns change over the lifespan, we investigated the effects of short sleep and age on empathic responses. In a randomized cross-over experimental design, healthy young and older volunteers (n = 47 aged 20-30 years and n = 39 aged 65-75 years) underwent functional magnetic resonance imaging (fMRI) after normal sleep or night sleep restricted to 3 hours. During fMRI, participants viewed pictures of needles pricking a hand (pain) or Q-tips touching a hand (control), a well-established paradigm to investigate empathy for pain. There was no main effect of sleep restriction on empathy. However, age and sleep interacted so that sleep restriction caused increased unpleasantness in older but not in young participants. Irrespective of sleep condition, older participants showed increased activity in angular gyrus, superior temporal sulcus and temporo-parietal junction compared to young. Speculatively, this could indicate that the older individuals adopted a more cognitive approach in response to others' pain. Our findings suggest that caution in generalizability across age groups is needed in further studies of sleep on social cognition and emotion.