A Motor Theory of Sleep-Wake Control: Arousal-Action Circuit.

Wakefulness, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep are characterized by distinct electroencephalogram (EEG), electromyogram (EMG), and autonomic profiles. The circuit mechanism coordinating these changes during sleep-wake transitions remains poorly understood. The past few years have witnessed rapid progress in the identification of REM and NREM sleep neurons, which constitute highly distributed networks spanning the forebrain, midbrain, and hindbrain. Here we propose an arousal-action circuit for sleep-wake control in which wakefulness is supported by separate arousal and action neurons, while REM and NREM sleep neurons are part of the central somatic and autonomic motor circuits. This model is well supported by the currently known sleep and wake neurons. It can also account for the EEG, EMG, and autonomic profiles of wake, REM, and NREM states and several key features of their transitions. The intimate association between the sleep and autonomic/somatic motor control circuits suggests that a primary function of sleep is to suppress motor activity.

A disinhibitory circuit mechanism explains a general principle of peak performance during mid-level arousal.

Perceptual decision-making is highly dependent on the momentary arousal state of the brain, which fluctuates over time on a scale of hours, minutes, and even seconds. The textbook relationship between momentary arousal and task performance is captured by an inverted U-shape, as put forward in the Yerkes-Dodson law. This law suggests optimal performance at moderate levels of arousal and impaired performance at low or high arousal levels. However, despite its popularity, the evidence for this relationship in humans is mixed at best. Here, we use pupil-indexed arousal and performance data from various perceptual decision-making tasks to provide converging evidence for the inverted U-shaped relationship between spontaneous arousal fluctuations and performance across different decision types (discrimination, detection) and sensory modalities (visual, auditory). To further understand this relationship, we built a neurobiologically plausible mechanistic model and show that it is possible to reproduce our findings by incorporating two types of interneurons that are both modulated by an arousal signal. The model architecture produces two dynamical regimes under the influence of arousal: one regime in which performance increases with arousal and another regime in which performance decreases with arousal, together forming an inverted U-shaped arousal-performance relationship. We conclude that the inverted U-shaped arousal-performance relationship is a general and robust property of sensory processing. It might be brought about by the influence of arousal on two types of interneurons that together act as a disinhibitory pathway for the neural populations that encode the available sensory evidence used for the decision.

Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus.

Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5-HT:5-hydroxytryptamine) neurons and decreased 5-HT activity was classically thought to increase aggression. However, recent studies challenge this 5-HT deficiency model, revealing a more complex role for the DRN 5-HT system in aggression. Furthermore, emerging evidence has shown that non-5-HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5-HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5-HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN-mediated aggression modulation.

SIK3-HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice.

Mammals exhibit circadian cycles of sleep and wakefulness under the control of the suprachiasmatic nucleus (SCN), such as the strong arousal phase-locked to the beginning of the dark phase in laboratory mice. Here, we demonstrate that salt-inducible kinase 3 (SIK3) deficiency in gamma-aminobutyric acid (GABA)-ergic neurons or neuromedin S (NMS)-producing neurons delayed the arousal peak phase and lengthened the behavioral circadian cycle under both 12-h light:12-h dark condition (LD) and constant dark condition (DD) without changing daily sleep amounts. In contrast, the induction of a gain-of-function mutant allele of Sik3 in GABAergic neurons exhibited advanced activity onset and a shorter circadian period. Loss of SIK3 in arginine vasopressin (AVP)-producing neurons lengthened the circadian cycle, but the arousal peak phase was similar to that in control mice. Heterozygous deficiency of histone deacetylase (HDAC) 4, a SIK3 substrate, shortened the circadian cycle, whereas mice with HDAC4 S245A, which is resistant to phosphorylation by SIK3, delayed the arousal peak phase. Phase-delayed core clock gene expressions were detected in the liver of mice lacking SIK3 in GABAergic neurons. These results suggest that the SIK3-HDAC4 pathway regulates the circadian period length and the timing of arousal through NMS-positive neurons in the SCN.

Double Dissociation of Spontaneous Alpha-Band Activity and Pupil-Linked Arousal on Additive and Multiplicative Perceptual Gain.

Perception is a probabilistic process dependent on external stimulus properties and one's internal state. However, which internal states influence perception and via what mechanisms remain debated. We studied how spontaneous alpha-band activity (8-13 Hz) and pupil fluctuations impact visual detection and confidence across stimulus contrast levels (i.e., the contrast response function, CRF). In human subjects of both sexes, we found that low prestimulus alpha power induced an "additive" shift in the CRF, whereby stimuli were reported present more frequently at all contrast levels, including contrast of zero (i.e., false alarms). Conversely, prestimulus pupil size had a "multiplicative" effect on detection such that stimuli occurring during large pupil states (putatively corresponding to higher arousal) were perceived more frequently as contrast increased. Signal detection modeling reveals that alpha power changes detection criteria equally across the CRF but not detection sensitivity (d'), whereas pupil-linked arousal modulated sensitivity, particularly for higher contrasts. Interestingly, pupil size and alpha power were positively correlated, meaning that some of the effect of alpha on detection may be mediated by pupil fluctuations. However, pupil-independent alpha still induced an additive shift in the CRF corresponding to a criterion effect. Our data imply that low alpha boosts detection and confidence by an additive factor, rather than by a multiplicative scaling of contrast responses, a profile which captures the effect of pupil-linked arousal. We suggest that alpha power and arousal fluctuations have dissociable effects on behavior. Alpha reflects the baseline level of visual excitability, which can vary independent of arousal.

Functionality of arousal-regulating brain circuitry at rest predicts human cognitive abilities.

Arousal state is regulated by subcortical neuromodulatory nuclei, such as locus coeruleus, which send wide-reaching projections to cortex. Whether higher-order cortical regions have the capacity to recruit neuromodulatory systems to aid cognition is unclear. Here, we hypothesized that select cortical regions activate the arousal system, which, in turn, modulates large-scale brain activity, creating a functional circuit predicting cognitive ability. We utilized the Human Connectome Project 7T functional magnetic resonance imaging dataset (n = 149), acquired at rest with simultaneous eye tracking, along with extensive cognitive assessment for each subject. First, we discovered select frontoparietal cortical regions that drive large-scale spontaneous brain activity specifically via engaging the arousal system. Second, we show that the functionality of the arousal circuit driven by bilateral posterior cingulate cortex (associated with the default mode network) predicts subjects' cognitive abilities. This suggests that a cortical region that is typically associated with self-referential processing supports cognition by regulating the arousal system.

Hypnotics on Obstructive Sleep Apnea Severity and Endotypes: A Systematic Review and Meta-Analysis.

RATIONALE: Low arousal threshold and poor muscle responsiveness are common determinants of obstructive sleep apnea (OSA). Hypnotics were hypothesized as an alternative OSA treatment via raising the arousal threshold and possibly genioglossus responsiveness. OBJECTIVES: Effect of common hypnotics on arousal threshold, OSA severity and genioglossus responsiveness. METHODS: We searched MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov for randomized clinical trials, and ran meta-analyses to determine the effect of oral hypnotics on arousal threshold, OSA severity and genioglossus responsiveness. GRADE was used to rate the quality of evidence (QoE). The association between post-treatment AHI and arousal threshold percent reductions was explored in individual patient data (IPD) metanalyses (overall sample and low arousal threshold subgroups). MEASUREMENTS AND MAIN RESULTS: Based on our analysis (27 studies; 25 for AHI, 11 for arousal threshold, 4 for genioglossus responsiveness), hypnotics minimally raised arousal threshold (mean difference [95% CI]: 2.7 [1.5, 3.8] cmH2O epiglottic pressure swings; moderate QoE), but did not change OSA severity (1.4 [3.5, 0.7] events/h; moderate QoE). IPD meta-analysis (N=114) showed no association between changes in arousal threshold and AHI, independent of low arousal threshold subgrouping. However, people with very-low arousal threshold or those who exhibited 0-25% arousal threshold increase from placebo experienced the greatest-yet still modest-post-treatment AHI reductions (10%). Hypnotics did not affect genioglossus responsiveness (high QoE). CONCLUSIONS: Further research testing or clinical use of hypnotics as OSA alternative treatments should be discouraged, unless in the presence of comorbid insomnia or as part of combination therapy in individuals with very-low arousal threshold.

Temporal relations between peripheral and central arousals in good and poor sleepers.

Good sleepers and patients with insomnia symptoms (poor sleepers) were tracked with two measures of arousal; conventional polysomnography (PSG) for electroencephalogram (EEG) assessed cortical arousals, and a peripheral arterial tonometry device was used for the detection of peripheral nervous system (PNS) arousals associated with vasoconstrictions. The relationship between central (cortical) and peripheral (autonomic) arousals was examined by evaluating their close temporal dynamics. Cortical arousals almost invariably were preceded and followed by peripheral activations, while large peripheral autonomic arousals were followed by cortical arousals only half of the time. The temporal contiguity of these two types of arousals was altered in poor sleepers, and poor sleepers displayed a higher number of cortical and peripheral arousals compared with good sleepers. Given the difference in the number of peripheral autonomic arousals between good and poor sleepers, an evaluation of such arousals could become a means of physiologically distinguishing poor sleepers.

Basolateral amygdala activation enhances object recognition memory by inhibiting anterior insular cortex activity.

Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.

Active neural coordination of motor behaviors with internal states.

The brain continuously coordinates skeletomuscular movements with internal physiological states like arousal, but how is this coordination achieved? One possibility is that the brain simply reacts to changes in external and/or internal signals. Another possibility is that it is actively coordinating both external and internal activities. We used functional ultrasound imaging to capture a large medial section of the brain, including multiple cortical and subcortical areas, in marmoset monkeys while monitoring their spontaneous movements and cardiac activity. By analyzing the causal ordering of these different time series, we found that information flowing from the brain to movements and heart-rate fluctuations were significantly greater than in the opposite direction. The brain areas involved in this external versus internal coordination were spatially distinct, but also extensively interconnected. Temporally, the brain alternated between network states for this regulation. These findings suggest that the brain's dynamics actively and efficiently coordinate motor behavior with internal physiology.

Pupil Dilation and Microsaccades Provide Complementary Insights into the Dynamics of Arousal and Instantaneous Attention during Effortful Listening.

Listening in noisy environments requires effort- the active engagement of attention and other cognitive abilities- as well as increased arousal. The ability to separately quantify the contribution of these components is key to understanding the dynamics of effort and how it may change across listening situations and in certain populations. We concurrently measured two types of ocular data in young participants (both sexes): pupil dilation (PD; thought to index arousal aspects of effort) and microsaccades (MS; hypothesized to reflect automatic visual exploratory sampling), while they performed a speech-in-noise task under high- (HL) and low- (LL) listening load conditions. Sentences were manipulated so that the behaviorally relevant information (keywords) appeared at the end (Experiment 1) or beginning (Experiment 2) of the sentence, resulting in different temporal demands on focused attention. In line with previous reports, PD effects were associated with increased dilation under load. We observed a sustained difference between HL and LL conditions, consistent with increased phasic and tonic arousal. Importantly we show that MS rate was also modulated by listening load. This was manifested as a reduced MS rate in HL relative to LL. Critically, in contrast to the sustained difference seen for PD, MS effects were localized in time, specifically during periods when demands on auditory attention were greatest. These results demonstrate that auditory selective attention interfaces with the mechanisms controlling MS generation, establishing MS as an informative measure, complementary to PD, with which to quantify the temporal dynamics of auditory attentional processing under effortful listening conditions.SIGNIFICANCE STATEMENT Listening effort, reflecting the "cognitive bandwidth" deployed to effectively process sound in adverse environments, contributes critically to listening success. Understanding listening effort and the processes involved in its allocation is a major challenge in auditory neuroscience. Here, we demonstrate that microsaccade rate can be used to index a specific subcomponent of listening effort, the allocation of instantaneous auditory attention, that is distinct from the modulation of arousal indexed by pupil dilation (currently the dominant measure of listening effort). These results reveal the push-pull process through which auditory attention interfaces with the (visual) attention network that controls microsaccades, establishing microsaccades as a powerful tool for measuring auditory attention and its deficits.

The Arousal-Related "Central Thalamus" Stimulation Site Simultaneously Innervates Multiple High-Level Frontal and Parietal Areas.

In human and nonhuman primates, deep brain stimulation applied at or near the internal medullary lamina of the thalamus [a region referred to as "central thalamus," (CT)], but not at nearby thalamic sites, elicits major changes in the level of consciousness, even in some minimally conscious brain-damaged patients. The mechanisms behind these effects remain mysterious, as the connections of CT had not been specifically mapped in primates. In marmoset monkeys (Callithrix jacchus) of both sexes, we labeled the axons originating from each of the various CT neuronal populations and analyzed their arborization patterns in the cerebral cortex and striatum. We report that, together, these CT populations innervate an array of high-level frontal, posterior parietal, and cingulate cortical areas. Some populations simultaneously target the frontal, parietal, and cingulate cortices, while others predominantly target the dorsal striatum. Our data indicate that CT stimulation can simultaneously engage a heterogeneous set of projection systems that, together, target the key nodes of the attention, executive control, and working-memory networks of the brain. Increased functional connectivity in these networks has been previously described as a signature of consciousness.SIGNIFICANCE STATEMENT In human and nonhuman primates, deep brain stimulation at a specific site near the internal medullary lamina of the thalamus ["central thalamus," (CT)] had been shown to restore arousal and awareness in anesthetized animals, as well as in some brain-damaged patients. The mechanisms behind these effects remain mysterious, as CT connections remain poorly defined in primates. In marmoset monkeys, we mapped with sensitive axon-labeling methods the pathways originated from CT. Our data indicate that stimulation applied in CT can simultaneously engage a heterogeneous set of projection systems that, together, target several key nodes of the attention, executive control, and working-memory networks of the brain. Increased functional connectivity in these networks has been previously described as a signature of consciousness.

Spatial representation of multidimensional information in emotional faces revealed by fMRI.

Face perception is a complex process that involves highly specialized procedures and mechanisms. Investigating into face perception can help us better understand how the brain processes fine-grained, multidimensional information. This research aimed to delve deeply into how different dimensions of facial information are represented in specific brain regions or through inter-regional connections via an implicit face recognition task. To capture the representation of various facial information in the brain, we employed support vector machine decoding, functional connectivity, and model-based representational similarity analysis on fMRI data, resulting in the identification of three crucial findings. Firstly, despite the implicit nature of the task, emotions were still represented in the brain, contrasting with all other facial information. Secondly, the connection between the medial amygdala and the parahippocampal gyrus was found to be essential for the representation of facial emotion in implicit tasks. Thirdly, in implicit tasks, arousal representation occurred in the parahippocampal gyrus, while valence depended on the connection between the primary visual cortex and the parahippocampal gyrus. In conclusion, these findings dissociate the neural mechanisms of emotional valence and arousal, revealing the precise spatial patterns of multidimensional information processing in faces.

Emotional processing impairments in patients with insula lesions following stroke.

Functional imaging has helped to understand the role of the human insula as a major processing network for integrating input with the current state of the body. However, these studies remain at a correlative level. Studies that have examined insula damage show lesion-specific performance deficits. Case reports have provided anecdotal evidence for deficits following insula damage, but group lesion studies offer a number of advances in providing evidence for functional representation of the insula. We conducted a systematic literature search to review group studies of patients with insula damage after stroke and identified 23 studies that tested emotional processing performance in these patients. Eight of these studies assessed emotional processing of visual (most commonly IAPS), auditory (e.g., prosody), somatosensory (emotional touch) and autonomic function (heart rate variability). Fifteen other studies looked at social processing, including emotional face recognition, gaming tasks and tests of empathy. Overall, there was a bias towards testing only patients with right-hemispheric lesions, making it difficult to consider hemisphere specificity. Although many studies included an overlay of lesion maps to characterise their patients, most did not differentiate lesion statistics between insula subunits and/or applied voxel-based associations between lesion location and impairment. This is probably due to small group sizes, which limit statistical comparisons. We conclude that multicentre analyses of lesion studies with comparable patients and performance tests are needed to definitively test the specific function of parts of the insula in emotional processing and social interaction.

A mammal and bird's-eye-view of the pupil during sleep and wakefulness.

Besides regulating the amount of light that reaches the retina, fluctuations in pupil size also occur in isoluminant conditions during accommodation, during movement and in relation to cognitive workload, attention and emotion. Recent studies in mammals and birds revealed that the pupils are also highly dynamic in the dark during sleep. However, despite exhibiting similar sleep states (rapid eye movement [REM] and non-REM [NREM] sleep), wake and sleep state-dependent changes in pupil size are opposite between mammals and birds, due in part to differences in the type (striated vs. smooth) and control of the iris muscles. Given the link between pupil dynamics and cognitive processes occurring during wakefulness, sleep-related changes in pupil size might indicate when related processes are occurring during sleep. Moreover, the divergent pupillary behaviour observed between mammals and birds raises the possibility that changes in pupil size in birds are a readout of processes not reflected in the mammalian pupil.

Functional connectivity between medial pulvinar and cortical networks as a predictor of arousal to noxious stimuli during sleep.

The interruption of sleep by a nociceptive stimulus is favoured by an increase in the pre-stimulus functional connectivity between sensory and higher level cortical areas. In addition, stimuli inducing arousal also trigger a widespread electroencephalographic (EEG) response reflecting the coordinated activation of a large cortical network. Because functional connectivity between distant cortical areas is thought to be underpinned by trans-thalamic connections involving associative thalamic nuclei, we investigated the possible involvement of one principal associative thalamic nucleus, the medial pulvinar (PuM), in the sleeper's responsiveness to nociceptive stimuli. Intra-cortical and intra-thalamic signals were analysed in 440 intracranial electroencephalographic (iEEG) segments during nocturnal sleep in eight epileptic patients receiving laser nociceptive stimuli. The spectral coherence between the PuM and 10 cortical regions grouped in networks was computed during 5 s before and 1 s after the nociceptive stimulus and contrasted according to the presence or absence of an arousal EEG response. Pre- and post-stimulus phase coherence between the PuM and all cortical networks was significantly increased in instances of arousal, both during N2 and paradoxical (rapid eye movement [REM]) sleep. Thalamo-cortical enhancement in coherence involved both sensory and higher level cortical networks and predominated in the pre-stimulus period. The association between pre-stimulus widespread increase in thalamo-cortical coherence and subsequent arousal suggests that the probability of sleep interruption by a noxious stimulus increases when it occurs during phases of enhanced trans-thalamic transfer of information between cortical areas.

The arousal level of consciousness required for working memory performance: An anaesthesia study.

Regarding the stage of arousal level required for working memory to function properly, limited studies have been conducted on changes in working memory performance when the arousal level of consciousness decreases. This study aimed to experimentally clarify the stages of consciousness necessary for optimal working memory function. In this experiment, the sedation levels were changed step-by-step using anaesthesia, and the performance accuracy during the execution of working memory was assessed using a dual-task paradigm. Participants were required to categorize and remember words in a specific target category. Categorization performance was measured across four different sedative phases: before anaesthesia (baseline), and deep, moderate and light stages of sedation. Short-delay recognition tasks were performed under these four sedative stages, followed by long-delay recognition tasks after participants recovered from sedation. The results of the short-delay recognition task showed that the performance was lowest at the deep stage. The performance of the moderate stage was lower than the baseline. In the long-delay recognition task, the performance under moderate sedation was lower than that under baseline and light sedation. In addition, the performance under light sedation was lower than that under baseline. These results suggest that task performance becomes difficult under half sedation and that transferring information to long-term memory is difficult even under one-quarter sedation.

Beat-to-beat cardiac repolarization lability increases during hypoxemia and arousals in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is associated with the progression of cardiovascular diseases, arrhythmias, and sudden cardiac death (SCD). However, the acute impacts of OSA and its consequences on heart function are not yet fully elucidated. We hypothesized that desaturation events acutely destabilize ventricular repolarization, and the presence of accompanying arousals magnifies this destabilization. Ventricular repolarization lability measures, comprising heart rate corrected QT (QTc), short-time-variability of QT (STVQT), and QT variability index (QTVI), were calculated before, during, and after 20,955 desaturations from lead II electrocardiography signals of 492 patients with suspected OSA (52% men). Variations in repolarization parameters were assessed during and after desaturations, both with and without accompanying arousals, and groupwise comparisons were performed based on desaturation duration and depth. Regression analyses were used to investigate the influence of confounding factors, comorbidities, and medications. The standard deviation (SD) of QT, mean QTc, SDQTc, and STVQT increased significantly (P < 0.01), whereas QTVI decreased (P < 0.01) during and after desaturations. The changes in SDQT, mean QTc, SDQTc, and QTVI were significantly amplified (P < 0.01) in the presence of accompanying arousals. Desaturation depth was an independent predictor of increased SDQTc (ß = 0.405, P < 0.01), STVQT (ß = 0.151, P < 0.01), and QTVI (ß = 0.009, P < 0.01) during desaturation. Desaturations cause acute changes in ventricular repolarization, with deeper desaturations and accompanying arousals independently contributing to increased ventricular repolarization lability. This may partially explain the increased risk of arrhythmias and SCD in patients with OSA, especially when the OSA phenotype includes high hypoxic load and fragmented sleep.NEW & NOTEWORTHY Nocturnal desaturations are associated with increased ventricular repolarization lability. Deeper desaturations with accompanying arousals increase the magnitude of alterations, independent of confounding factors, comorbidities, and medications. Changes associated with desaturations can partially explain the increased risk of arrhythmias and sudden cardiac death in patients with OSA, especially in patients with high hypoxic load and fragmented sleep. This highlights the importance of detailed electrocardiogram analytics for patients with OSA.

The neurobiology of aesthetic chills: How bodily sensations shape emotional experiences.

The phenomenon of aesthetic chills-shivers and goosebumps associated with either rewarding or threatening stimuli-offers a unique window into the brain basis of conscious reward because of their universal nature and simultaneous subjective and physical counterparts. Elucidating the neural mechanisms underlying aesthetic chills can reveal fundamental insights about emotion, consciousness, and the embodied mind. What is the precise timing and mechanism of bodily feedback in emotional experience? How are conscious feelings and motivations generated from interoceptive predictions? What is the role of uncertainty and precision signaling in shaping emotions? How does the brain distinguish and balance processing of rewards versus threats? We review neuroimaging evidence and highlight key questions for understanding how bodily sensations shape conscious feelings. This research stands to advance models of brain-body interactions shaping affect and may lead to novel nonpharmacological interventions for disorders of motivation and pleasure.

High prevalence of severe sleep cycle disruption in de novo acromegaly and underdiagnosis by common clinical screening tools: A prospective, observational, cross-sectional study.

CONTEXT: Although sleep disordered breathing (SDB) is well-recognised in acromegaly, most studies have reported heterogeneous, often heavily treated, groups and few have performed detailed sleep phenotyping at presentation. OBJECTIVE: To study SDB using the gold standard of polysomnography, in the largest group of newly-diagnosed, treatment-naïve patients with acromegaly. SETTING AND PATIENTS: 40 patients [22 males, 18 females; mean age 54 years (range 23-78)], were studied to: (i) establish the prevalence and severity of SDB (ii) assess the reliability of commonly employed screening tools [Epworth Sleepiness Scale (ESS) and overnight oxygen desaturation index (DI)] to detect SDB (iii) determine the extent to which sleep architecture is disrupted. RESULTS: Obstructive sleep apnoea (OSA), defined by the apnoea-hypopnoea index (AHI), was present in 79% of subjects (mild, n = 12; moderate, n = 5; severe, n = 14). However, in these individuals with OSA by AHI criteria, ESS (positive in 35% [n = 11]) and DI (positive in 71%: mild, n = 11; moderate, n = 6; severe, n = 5) markedly underestimated its prevalence/extent. Seventy-eight percent of patients exhibited increased arousal, with marked disruption of the sleep cycle, despite most (82%) having normal total time asleep. Fourteen patients spent longer in stage 1 sleep. Deeper sleep stages were severely attenuated in many subjects (reduced stage 2, n = 18; reduced slow wave sleep, n = 24; reduced rapid eye movement sleep, n = 32). CONCLUSION: Our study provides strong support for clinical guidelines that recommend screening for sleep apnoea syndrome in patients with newly-diagnosed acromegaly. Importantly, however, it highlights shortcomings in commonly recommended screening tools (questionnaires, desaturation index) and demonstrates the added value of polysomnography to allow timely detection of obstructive sleep apnoea and associated sleep cycle disruption.