Human REM sleep: influence on feeding behaviour, with clinical implications

Accepted Manuscript Title: Human REM sleep: influence on feeding behaviour, with clinical implications Author: James A. Horne PII: DOI: Reference:

S1389-9457(15)00706-6 http://dx.doi.org/doi:10.1016/j.sleep.2015.04.002 SLEEP 2736

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Sleep Medicine

Received date: Revised date: Accepted date:

5-12-2014 12-3-2015 9-4-2015

Please cite this article as: James A. Horne, Human REM sleep: influence on feeding behaviour, with clinical implications, Sleep Medicine (2015), http://dx.doi.org/doi:10.1016/j.sleep.2015.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Human REM Sleep: Influence on Feeding Behaviour, with Clinical Implications

James A. Horne

Sleep Research Centre Loughborough University Loughborough, Leicestershire, LE11 3TU, UK Tel +44 (0)792 508 6112 Email – [email protected]

The author has neither financial interest in, nor financial support for writing this article

10th March 2015

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2 ABSTRACT Rapid Eye Movement sleep (REM) shares many underlying mechanisms with wakefulness, to a much greater extent than does nonREM, especially those relating to feeding behaviours, appetite, curiosity, exploratory (locomotor) activites, as well as aspects of emotions, particularly ‘fear-extinction’. REM is most evident in infancy, thereafter declining in what seems to be dispensable manner that largely reciprocates increasing wakefulness. However, human adults retain more REM than do other mammals, where for us it is most abundant during our usual final REM period (fREMP) of the night, nearing wakefulness. The case is made that our REM is unusual, and that: i) fREMP retains this ‘dispensability’, acting as a proxy for wakefulness, able to be forfeited (without REM rebound) and substituted by physical activity (locomotion) when pressures of wakefulness increase ; ii) REM’s atonia (inhibited motor output) may be a proxy for this locomotion iii) our nocturnal sleep typically develops into a physiological fast, especially during fREMP, which is also an appetite suppressant; iv) REM may have ‘anti-obesity’ properties, and that loss of fREMP may well enhance appetite and contribute to weight gain (‘overeating’) in habitually short sleepers; v) as we also select foods for their hedonic (emotional) values, REM may be integral to developing food preferences and dislikes; vii) REM seems to have wider influences in regulating energy balance in terms of exercise ‘substitution’ and energy (body heat) retention. Avenues for further research are proposed, linking REM with feeding behaviours, including eating disorders, and effects of REM suppressant medications.

KEYWORDS: REM sleep, energy balance, appetite, emotions, feeding behaviours, food preferences, obesity

HIGHLIGHTS (bullet points)

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REM shares many mechanisms with wakefulness, especially with feeding and exploratory behaviours

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Our final REM period (fREMP) is a proxy for wakefulness, forfeitable and substituted by locomotion

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fREMP is a fasting state with appetite suppression and ‘anti-obesity’ properties.

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REM’s emotional attributes may be integral to developing food preferences and dislikes

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REM has wider effects on energy balance with: body heat conservation and atonia as an exercise proxy

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Proposed research links REM with eating disorders and variable weight gains with antidepressants

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Proposed research links REM with eating disorders and variable weight gains with antidepressants

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3 1.Overview Recent brain imaging and related findings with human sleep help provide a wider perspective on the functions of Rapid Eye Movement sleep (REM), especially when seen in the light of other contemporary findings outside sleep research. Together, these afford a wider perspective on this still enigmatic form of sleep. As will be seen, and compared with non-REM sleep, REM has notably more underlying mechanisms in common with wakefulness, particularly, with those involved in exploratory and feeding behaviours. Other recent evidence points to human REM having a significant role in regulating waking emotional tone, especially in modulating fear responses. One explanation integrating these findings for REM derives from it being ‘wake-like’, and that for most mammals in their natural environment, wakefulness is preoccupied by exploration mostly for food, that often necessitates the balancing of curiosity required for this exploration against the potential for encountering danger with its implicit fear. In these respects locomotor activity may have key roles [1], with the inhibited motor output (atonia) during REM being a substitute for this locomotion. As exercise and energy expenditure are integrated within the overall control by the brain of energy balance, our final REM period (fREMP) might be seen as a ‘proxy’ for wakefulness, and it is possible that the atonia also acts as a form of substitute for this role of waking exercise. Thus, in general, REM is seen to be integral to maintaining energy balance in its widest sense, including in having a thermoregulatory role with energy (body heat) conservation [1,2]. The present account focuses on humans, as our adult REM has some features unusual amongst mammals. The first derives from us adults having retained during our evolution, many infant ape characteristics (ie - we are neotenous), seen with our gross anatomy and our high degree of adult brain plasticity, learning ability, curiosity and exploratory behaviour [3]. Whereas REM is preponderant in mammalian infancy, thereafter declining by what seems to be in a reciprocal manner with increasing wakefulness, we adults retain more REM into adulthood than do most other mammals. Moreover, we seem to have retained more of this infant-like ‘dispensable REM’ which, it is argued, predominates in fREMP, when actual sleep need has declined. Second, again unusual amongst mammals (see 8.1), and for many of us, our last meal of the day is some hours before sleep onset, with the latter part of nocturnal sleep typically developing into a physiological fasting state, culminating towards morning waking, when it is common for well over 8 hours to have elapsed since the previous meal, and when REM (ie fREMP) is at its most abundant and intense, and able to suppress appetite. As fREMP can be forfeited (without REM rebound) and replaced by wakefulness (depending on waking pressures), especially if this entails locomotion, this could result in more feeding activity and its (emotional) gratification; thus to a positive energy balance. As will be seen, this approach provides for relatively unexplored avenues for research with human REM. For example, REM-associated mechanisms (eg hypocretin and leptin) also ‘protect’ against excess fat deposition, thus it is possible that the apparent weight gain and greater prevalence of obesity in ‘short sleepers’ might be at least in part be due to their having ‘lost’ their fREMP, which might otherwise be ‘anti-obesity’. Interestingly, evidence from outside sleep research increasingly points to obesity in humans having a wider neuropsychological basis, linked to mood disturbance, psychosocial stress, and reward systems affecting appetite and palatability of foods [4]. These systems also happen to be mediated by the newly discovered neuropeptides visfatin and nesfatin-1, that are also linked to REM mechanisms (see 4).

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4 The following account begins with a summary of the wake-like, feeding and emotion associations for REM, before proceeding to integrate these into a fuller picture, also having clinical relevance. However, it should be noted that this account is oriented towards a wider functional approach to human REM, albeit acknowledging that REM comprises various integral mechanisms, for example, described elsewhere as ‘flip-flop’ [5,6] as well as separate REM ‘on’, ‘off’ and ‘maintenance’ systems [7]. The orchestration of these particular systems is beyond this present perspective and its more general review, as is the topic of dreaming, especially as REM and dreaming involve separate brain systems [8]. 2.Similarities with Wakefulness During REM several brain areas show activity patterns similar to those of wakefulness. This can be seen using functional magnetic resonance imaging (fMRI) within, for example, the: pontine tegmentum, thalamus, basal forebrain, amygdala, hippocampus, anterior cingulate cortex (ACC), and temporo-occipital areas [9]. Also in humans, and described in detail elsewhere [1] this similarity is further shown electrophysiologically by: pontinegenicuate-occipital (PGO) like activity [9,10] indicative of orientation responses to novel stimuli [11]; cortical gamma activity (reflecting behavioural integration), sensorimotor rhythm (passive ‘mirroring’ of actions), default mode network activity and hippocampal theta activity (also important in ‘place’ memory); and multisensory recruitment with integrated perception [12,13] - also manifested by dreaming. But, clearly, REM is not wakefulness, and activities in other brain areas differentiate the two states [9]. Nevertheless, these similarities are noteworthy and distinct from non-REM. Findings with cats [12] show their behaviour during REM also to be wake like, albeit blocked by the atonia accompanying what otherwise would be a voluntary motor output. Elimination of the atonia by lesions to pontine noradrenergic neurones produce stereotyped waking behaviours (eg. searching, reaching and grasping) during REM, but in the absence of any external stimulation. Although the cat seems excited, often reflecting ‘flight or fight’ behaviour, sympathetic activation (eg. indicative of fearfulness) is blocked.

3. Locomotion In wakefulness, and especially with humans, locomotion is interlinked with cognitions and emotions, to further promote brain plasticity, and as Kemperman et al [14] argue in their recent review (outside the area of sleep),

“locomotion actually serves as an intrinsic feedback mechanism, signalling to the brain, including its neural precursor cells, increasing the likelihood of cognitive challenges. In the wild (other than in front of a TV), no separation of physical and cognitive activity occurs. Physical activity might thus be much more than a generally healthy garnish to leading "an active life" but an evolutionarily fundamental aspect of ‘activity’ which is needed to provide the brain and its systems of plastic adaptation with the appropriate” p1. In rats and cats [15-17], REM deprivation produced by gentle handling leads to no REM rebound, indicating the apparent substitution of REM by physical movement, and that exercise seems to be ‘REM-loss protective’ [18]. In these respects the inhibited motor output (atonia) during REM may be a form of substitute for this locomotion. Other accumulating evidence points to locomotion having a strong influence on brain plasticity and cognition, particularly via the neuroprotective actions of brain derived neurotrophic factor (BDNF) in the hippocampus [19,20]. BDNF is also influenced by feedback from muscles [21], and in turn also influences energy balance [22]. The hippocampus, also active in REM, is not only critical to the formation of long-term Page 4 of 20

5 memories (particularly episodic memories associated with personal events and related emotions), but also to spatial navigation and the creation of a ‘cognitive map’ [23-25]. However, much of our understanding about this region is from the rat, including that for ‘place neurones’ within the hippocampus, firing when a waking animal passes through a known part of its environment. Thus, remembering locations in terms of, for example ‘encounters with food’ may involve REM, including associated emotional aspects, as will now be seen. 4. REM Mechanisms in Common with Feeding For mammals in general, there are various brain mechanisms and substances active in REM, not only involved with maintaining arousal, but in the control of appetite, feeding behaviour and energy balance. For example, this commonality between REM and feeding mechanisms applies to: the parabrachial nucleus [26] integrating signals from several brain regions that bidirectionally modulate feeding and body weight [27], especially appetite and its suppression [28]; the ACC, which in rodents mediates food foraging-related behaviours [29]; hypothalamic hypocretin and melanin concentrating hormone (MCH – [30-33], the adipose tissue derived cytokines, leptin and visfatin [30], and the recently discovered satiety molecule, nesfatin-1, involved with appetite, food intake and body weight regulation [34], which is co-expressed with MCH activity [33-35]. Interestingly, in rodents [33], the usual REM rebound following REM deprivation is blocked by nesfatin-1 antiserum, leaving nonREM unaffected. Other recently identified neuropeptides triggering satiety as well as increasing REM, are described by Méndez-Díaz [36] in their extensive review. In waking animals, hypocretin neurones promote arousal [37], being maximally active during exploratory behaviour [38], to the extent that Rogers et al [39] concluded that the hypocretin system orchestrates an “integrated set of reactions which function to rectify nutritional status ..finding and ingesting food without oneself becoming a meal for someone else” (p 303). A similar conclusion was reached, earlier, by Willie et al [40]. Several recent human studies have also linked REM with feeding behaviour. In an acute sleep curtailment study, Schechter et al [41] reported an inverse association between REM sleep duration and hunger, with REM also inversely related to subsequent carbohydrate intake. Moreover, Gonnissen et al [42] found that reduced REM, as a result of generalised sleep fragmentation in healthy men, did not affect blood glucose levels, but shifted the dynamics of waking blood insulin and glucagon-like peptide-1 concentrations, that together caused declines in subjective ‘fullness’ scores and increased the desire for snacking. The authors concluded that such effects promote increased food intake; thus contributing to a positive energy balance. In a larger study on human volunteers, Hayes et al [30] found that REM loss due to sleep restriction was linked to significant changes in plasma levels of both and leptin. Other marked links between REM and feeding behaviour are seen in the circadian and ultradian rhythmicities of REM, with such links being much less evident with nonREM [43]. Kleitman [44] referred to this in humans as the basic rest activity cycle (BRAC), integrating rhythmic feeding behaviour with REM. At least for other mammals, and apart from light-darkness being a powerful circadian zeitgeber affecting REM, so is the time of day when daily food availability is at its most propitious [45-46]. These food entrainable oscillators [45] also influence food anticipatory behaviours [47,48] which, in wakefulness, and at least in rodents, are accompanied by a transient rise in brain temperature produced by brown adipose tissue (BAT) thermogenesis, which is a component of their BRAC. This mechanism enables heightened arousal and faster feeding responses [49,50]. Page 5 of 20

6 Similar rises in brain temperature (as seen with hypothalamic temperature Thyp – [51]) are evident during REM in a variety of mammals [2]. Although this REM-related Thyp rise has been viewed by Parmeggiani [51] as a failure of thermoregulation, there is an alternative explanation, as this change is associated with a generalised vasoconstriction within thermolytic skin regions, leading to body heat retention (energy conservation). In turn, this would facilitate a reduced need for energy (food) intake [2, 52]. However, compared with smaller mammals such as the cat (more so with the rat), we humans have a much smaller body surface area to volume ratio, leading to a considerably greater thermal inertia, to the extent that, for us, a body core temperature rise attributable to REM would be more difficult to determine. Interestingly, the thermoregulatory changes occurring in human adult REM are reminiscent of that found in waking infants, inasmuch that in neither case can shivering or sweating occur, although BAT thermogenesis remains quite functional and effective [2,52]. Also worth noting is that, at least in smaller non-human mammals, REM is facilitated by a warm ambient environment [53]. For example, in rodents, three days of exposure to a warmer environment, led to a 28% increase in REM per 24h, compared with only a 5% increase in total sleep time [54]. In sum, as a warm environment also reduces heat loss, thus decreasing the need for (food) energy input, so lessening both appetite and the need to find food (with its accompanying risks), then such extra REM would further contribute to survival, and maybe provide for other waking behaviours relating to reproductive success. Irrespective of REM, ingestive behaviour is itself a complex field, and Schneider et al [55] point out in their recent extensive review of this behaviour, outside the field of sleep, that gaps in our knowledge remain, particularly with the consummatory act of eating, and for decisions about when and how much to eat. Clearly, any associations between REM, appetite, foraging for food and exploratory behaviour must also be complex. For example, take the links between hypothalmic hypocretin, obesity resistance [56] and the promotion of exploratory behaviour. Inasmuch that REM deprivation, here, might depress hypocretin levels in humans, this would accentuate feeding behaviour and, depending on the ease and availability of food, lead to positive energy balance and fat deposition. However, hypocretin has complex actions, able to promote both feeding and energy expenditure, depending on the activities of other mechanisms including leptin signalling and BAT thermogensis, that together also affect white fat deposition [57]. The latest review, by Teske et al [58], also outside the field of sleep, of mechanisms underlying obesity resistance, notes that elevated hypocretin signalling is associated with high levels of spontaneous physical activity, as well as having wider ‘anti-obesity’ effects. Thus, returning to the topic REM’s atonia, this could be contributing to this anti-obesity effect in a subtle way, maybe in re-calibrating energy balance, despite there being little extra energy expenditure (VO2 uptake) during human REM compared with stage 2 sleep [eg 59]. When considering whether REM reduction promotes a positive energy balance, it should be noted that in humans, visceral and subcutaneous fat deposition depend on different processes. Whereas subcutaneous fat is largely absent in other adult primates, interestingly, the only other mammals to have this form of fat (rather than the more usual visceral fat) are marine mammals, especially the cetacea and certain members of the pinnepedia. In the former there is no evidence of REM, and in the latter REM is absent when the animal is

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7 feeding and sleeping at sea, for many days. Although REM reappears when it returns to sleep on land, there is no REM rebound [60,61]. 4. REM and Emotions The heightened activity of the amygdala during REM is evident electrophysiologically in cats, with Morrison et al [62] describing this as the setting of ‘emotional tone’. In humans and in wakefulness at least, the amygdala also helps determine the emotional significances of complex social interactions [63] and contributes to the organization of defence reactions [64], possibly through interactions with the orbitofrontal cortex, which is also particularly active during human REM [65-67]. This latter brain region contributes to the assimilation and understanding of one’s own emotions, as well as with us being able to respond appropriately to the emotions of others, especially under changing situations. Vandekerckhove and Cluydts [68], in their recent review of the ‘emotional brain and sleep’, which largely focuses on humans, they argue that the increased activities of limbic structures during REM, coupled with apparent waking levels of activity in the medial prefrontal cortex, but with hypoactive dorsolateral prefrontal activity, point to a key role for REM in adaptive coping (consolidation) of the continuous stream of emotional events during wakefulness. Another extensive review, by Rasch and Born [69], is more specific in proposing that this consolidation in REM represents a stabilisation of emotional memories that have been previously transformed during slow wave sleep (SWS). Other findings [70] show that REM is associated with an overnight dissipation of amygdala activity in response to previous emotional experiences, leading to reduced subjective emotionality the next day. This process, otherwise known as ‘fear extinction’ [71,72], is positively correlated [73] with the preceding time spent in REM. Moreover, REM-associated dreaming also seems to have a role in the consolidation of memory traces having a high emotional value [74], particularly those involving mood, risktaking and compulsive behaviours [75]. Other brain regions associated with emotional tone, similarly active in human REM and wakefulness (but not in non-REM), are the ACC and hippocampus [9,68]. The ACC is also critical in modulating fear memories [76]. In humans, during both wakefulness and REM, the ACC displays similar EEG theta activity, leading Nishida et al [77] to conclude that ‘the ACC could be related to particular psychological functions in wakefulness and in REM sleep’ (p331). And, more recently, Sheth et al [78] reported that in wakefulness at least, and in humans, the ACC is involved with adaptation to conflict between competing responses. Other findings point to the waking ACC encoding the average value of the foraging environment and cost of foraging [79]. The ACC is also activated by curiosity, with the relief of this curiosity being rewarding [3]. This latter effect is further reflected by hippocampal activation and enhanced incidental memory [3]. Moreover, in animals, the ACC sustains wakefulness in a novel environment [80] and encodes the cost of foraging actions [81-83], and in the primate, (Macaca mulatta) the ACC is integral to decisions when to leave a depleted food resource and forage at another [84]. The ACC is closely linked to the ventromedial prefrontal cortex (vmPFC), associated with the control of voluntary actions [85] and fear conditioning, as has been recently reported [86] with humans. Here, vmPFC activity is predictive of subsequent fear memory consolidation, with a significant positive correlation between this activity during fear conditioning and subsequent REM sleep. In human wakefulness, at least, the vmPFC Page 7 of 20

8 helps determine between the alternative options of foraging or wider aspects of comparative decision-making [79] and, to the extent this is reflected within REM, it suggest that fREMP ‘helps decide’ on the mode of subsequent wakening behaviour in terms of feeding and wider aspects of exploratoration; both of which necessitate curiosity, tempered by the risk of encountering and dealing with danger (ie. fear responses). Given that exploratory behaviour (with inherent curiosity, fears and related emotions) involves the ACC, vmPFC, amygdala, and hippocampus, this could enable the creation (learning) of what might be termed a mental map of the location of those foods having strong positive or negative emotional associations, which together are processes potentially facilitated by REM. Moreover, as locomotion would be integral to these processes, then the atonia could, again, be implicated here. 6.Questionable Relevance of Animal Studies of Total REM Deprivation Extreme manipulations of REM deprivation in laboratory rodents leads to their excessive eating (hyperphagia), coupled with weight loss and thermoregulatory failures (mainly thermolysis), leading to septicaemia and death. However, this probably has little or no bearing on the current perspective on REM, as these methodologies are too severe, with ‘stress controls’ usually being inadequate [2]. Although there are huge REM rebounds if these animals are allowed to recover, this is also probably an artefact of the stressful methodology [87,88]. That is, animals are continuously exposed to light, an open field, and surrounded by water, all of which they would normally avoid. Thus, if REM helps moderate fear [88], and with these procedures being particularly ‘fearful’, then the animal is confronted with a double blow: loss of this REM related fear-reduction coping mechanism as well as the prolonged exposure to the stress of the procedure itself, unlike the control animals that can obtain REM and, hence, the coping mechanism. Consequently, the very large REM rebounds, here, would accommodate an excessive need of ‘fear reduction’. More benign REM deprivation methods on similar animals [89, 90], lead to only small REM rebounds. Unfortunately, little is known about thermoregulation or feeding activities in these latter studies. 7.Interim Summary The case is being made that: a) our REM is associated with the modulation of both feeding and emotional behaviours that can be linked together to influence energy balance; b) the atonia acts a substitute for locomotor activity which is integral to the cognitive aspects of this influence; c) our fREMP or its absence has a particular influence on subsequent wakefulness in terms of food seeking and its ‘emotional’ gratification; d) fREMP may have anti-obesity properties 8. Human REM, Feeding, Appetite and Emotions 8.1 Human Sleep-Fast – This was outlined earlier, and the reason why our nocturnal sleep is unusual amongst mammals in typically developing into a physiological fasting state [52], is that we are ‘meal eaters. Carnivores are ‘gorgers’ whereby complete digestion of large quantities high protein and fat intake can take well over 12h, with absorption continuing throughout sleep, as it does with herbivores (especially ruminants), when complete digestion of grasses etc can take days. Rodents are ’nibblers’ (especially in the laboratory), periodically waking up during sleep periods in order to feed. In none of these latter cases does sleep develop into a fast, which is likely to be a factor in the slow wave sleep-related human growth hormone (hGH) surge in us adults, that is mostly absent in these other adult mammals. Such a surge protects against the fast by liberating fats/lipids as Page 8 of 20

9 alternative energy sources and, more importantly, slows down protein turnover and thus spares protein as a further ‘fall-back’ energy supply [52]. As noted, fREMP is phasically more intense [9,10] as well as more abundant than earlier REMPs, which might well provide for a greater suppression of appetite, especially when food is plentiful and with less need to expend energy in finding food. An interesting finding by Siegel [91], with cats, noted that on a day to day basis REM was negatively correlated with subsequent food intake. However, this finding was not confirmed by another group [92], again with cats. Unfortunately, despite the ambiguous outcome, no further studies seem to have ensued. 8.2 Short Sleep, Appetite and Obesity – Acute sleep restriction in healthy young adults, to four hours a night, is associated with various metabolic changes, largely involving increasing insulin resistance and glucose intolerance [cf. 93]. But this level of sleep restriction is extreme, virtually unknown in habitual sleepers, and so one must be cautious in generalising these experimental findings as a cause of metabolic syndrome, diabetes and obesity in habitual short sleepers [cf. 94-96], as is often claimed [97]. It should be noted that a higher incidence of obesity is mostly confined to those habitually sleeping <5h [cf. 94,95], who comprise only about 58% of the normal adult population, and whose sleep could be considered as abnormally short. Other acute, but not so severe night sleep restrictions to 5-5.5h (resulting in the loss of fREMP) produce not only marked feelings of hunger, but the caloric content of the ad lib food consumed is well in excess of the energy difference between being asleep and resting wakefulness at that time [98,99]. More specifically, Gonnissen et al [42] (see 4 above) concluded that REM sleep loss during their one night study of sleep fragmentation was a key factor in the increased snacking behaviour by participants. Inasmuch that the usual fREMP commences at around the 6h point of the typical adult’s night sleep, and would be absent in the habitual <6h sleeper, it might have otherwise suppressed appetite and desire for food. That is, its loss might unmask hunger and appetite, even increase the urge to find food and eat, as this might ‘subconsciously’ indicate food shortages and a need to spend more time in foraging. However, if food is readily available with minimal energy expenditure, then there is potential for a positive energy balance which, if habitual, could lead to obesity. Interestingly, in examining obesity and short sleep in children and adolescents, Liu et al [100] concluded that one hour less of REM sleep was associated with about a three-fold increase in risk of obesity in these groups, which the authors specifically attributed to reduced REM sleep. However, on a cautious note, when assessing obesity in terms of fat deposition it is important to note, again, that visceral and sub-cutaneous fat depositions involve different mechanisms (see 4), which is why when considering BMI, waist circumference needs to be considered as an important, albeit often overlooked, additional measure in studies attributing links between sleep duration and obesity. In pre-diabetic states (eg metabolic syndrome) it is visceral fat that is of greater concern to health.

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10 8.3 Food Preferences– Our individual (idiosyncratic) food preferences often have emotional associations in terms of like and dislike, even desire, maybe implicating REM, given its role with emotions. Moreover, we eat palatable food for its hedonic (gourmet) properties, independent of energy status. As Kenny [101] recently pointed out in his review (outside the field of sleep) comparing various homeostatic mechanisms of feeding, much less is known about how hedonic systems in the brain influence food intake. He described how excessive consumption of palatable food can trigger neuroadaptive responses in brain reward circuits within the orbitofrontal frontal cortex, amygdala, and ACC. As noted earlier, these areas also happen to be active in REM. Thus, there would seem to be potential, here, to investigate how or whether REM suppression or other manipulations of REM also affect our food preferences. 8.4 Nutrigenomics and Epigenesis – Nutrients are able to signal specific gut, brain and other cells about diet status, and this new discipline concerns the interactions between food constituents and gene expression (via epigenesis), resulting in phenotypic change [cf: 102]. This mechanism translates information about the dietary environment, via transcription factors able to change gene and protein expression, including those from altered diets, to produce ‘dietary signatures’ resulting in homeostatic changes [102]. Nutrigenomics may also have wider implications for REM, maybe with the incorporation of the olfactory system. A role for REM in epigenesis was postulated some years ago by Jouvet [103] who proposed that REM is involved with epigenetic changes of a wider nature, as part of what he called ‘psychological indivuation’. This allowed the organism to adapt to more specific environmental circumstances. However, for him this was not a rapid interaction between REM and learning as is often seen to be the case, nowadays, but involved gradual, iterative modifications of more complex behaviours, maybe over weeks. Thus, a neutrigenomic approach to human REM, whereby REM maybe fine-tunes what we eat, affects taste/olfactory preferences and/or reinforces emotional attachment to foodstuffs, may also be an area for potential exploration. 8.5 Enhancing REM by increased glucose availability during sleep - Benedict [104] reported that the most notable effect of continuous glucose infusion during nocturnal sleep in healthy adults was a significant prolongation of REM at the expense of stage 2 sleep, particularly in the second half of sleep. This was within a 2 x 2 design, saline vs glucose and wake vs sleep. As sleep was always terminated after 7.5h, it is not known what would have happened with sleep thereafter. Some years ago we [105] found, also in humans, that carbohydrate loading by mouth (with added fat to delay gastric emptying) just prior to a night’s sleep led to a significant (27%) increase in REM, again mostly in the second half of the night (sleep was terminated after 8h), and when blood glucose levels still remained higher than usual. Both these studies would have ameliorated a sleep fast and lessened the need to find food. Despite these limited findings, it seems that carbohydrate loading before or during sleep, as a potential method for extending REM, and how this might impact on subsequent behaviours in terms of eating or mood (see 8.6) may well be another area worthy of further exploration. Indications of an inverse relationship between REM and subsequent food intake, on a daily basis, but in cats, was noted in 8.1. 8.6 REM Suppression by Antidepressants and Eating Behaviour - Most antidepressant medications suppress REM by about 30%, often for many weeks [cf.106], but resulting in only a nominal REM rebound in comparison with the total of that lost. However, REM suppression, here, is usually not the result of a shortening of sleep with the loss of fREMP, but is a diffuse effect throughout the sleep period, as seen, for example, in a long term Page 10 of 20

11 study on depressed patients [107], where phenelzine removed almost all REM (from about 16% to 4% of total sleep) for 3-6 months. REM seemed to be replaced by stage 2 sleep and, in particular, interim wakefulness (from about 15% to about 26% of total sleep). The authors noted that this “may be evidence for compensatory REM mechanisms occurring during wakefulness” (p S66). No mention was made of changes to eating behaviour or body weight, here. Whilst some antidepressants are linked to weight gains in humans, the extent to which this is associated with REM suppression is unclear [cf. 108], and not all antidepressants suppress REM (although most do); moreover, nonREM can also be suppressed. For example, whereas clomipramine and mirtazapine lead to substantial food craving, particularly of carbohydrates, and with weight gain [109], mirtazapine also markedly affects non-REM. Nevertheless, there remains the novel opportunity to investigate whether the differences in eating habits and weight gain associated with these antidepressants are reflected by potential differences in the distribution of REM over the sleep period. Also, the extent of REM suppression by these medicines might well be affected by evening snacking and carbohydrate intake that might antagonise REM suppression, as noted (8.5). 8.7 Human Starvation - The only sleep study of acute starvation (four days) in healthy young adults [110], found the greatest effect to be a loss of REM. Of course, if human starvation becomes chronic and foraging becomes pointless with a wasted expenditure of energy for no gain, the feeling of hunger disappears and people seem to spend much more time in lassitude including sleeping [cf. 111]. But nothing is known about the status of REM sleep under such extreme circumstances. Laboratory studies of food deprivation in rodents have reported that the most noticeable effect to be a marked reduction in REM [32]. 8.8 Anorexia Nervosa – This complex disorder is accompanied by a marked loss of REM in the second half of the night, substituted by wakefulness and often heightened waking locomotion [112]; subsequent weight gain reverses these effects. However, whether this locomotion could be a manifestation of ‘sublimated foraging’, is a matter for speculation, but maybe a perspective worth pursuing. Moreover, if REM influences food preferences (8.3), then therapeutic manipulations of REM, here, might be another avenue to explore. 8.9 Narcolepsy – This disorder, which usually involves cataplexy, includes gross disruption of REM, although it might not be a REM disorder per se. Apart from daytime sudden, spontaneous episodes of sleep and/or cataplexy, there is usually grossly disturbed nocturnal sleep, and sleep paralysis accompanied by hypnagogic hallucinations. Often (but not always), and within a few minutes of sleep onset, REM appears as a ‘sleep onset REMP – SOREMP’. Narcolepsy-cataplexy is closely associated with abnormally low brain hypocretin levels, seen with depleted hypocretin-1 in the CSF. Given the complexity of this disorder, the extent to which its REM characteristics accord with the present perspective must remain speculative, despite the consistent finding that these patients are typically overweight, and with a much higher than normal incidence of obesity. Although patients are often hypophagic, with a daily calorie intake well below that of controls [113], this remains a puzzle, and cannot be attributed simply to ‘lethargy, for example, as other factors such as spontaneous snacking behaviour are often overlooked. However, a finding maybe of a wider interest in relation the present review is that these patients often show olfactory dysfunction and impaired odour identification [114], which could impact on appetite, food preferences and eating behaviour. Measurement of odour identification is quite a simple

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12 procedure using standardised tests and would be worth exploring, even under scenarios 8.2, 8.3, 8.6, and 8.8 above. 9. Conclusions We live in an environment unlike that of only 20 or so generations ago, with our survival and waking dangers having changed towards a much safer society, and being surrounded by so much choice of easily available foods. Similarly, the extent to which our sleep interacts with these needs will have changed somewhat, although the more ‘hard wired’ underlying control mechanisms may still in the process of adapting, including the extent to which our sleep might contribute to the control of energy balance. This particularly applies to REM, which seems to be ‘wake like’ and, for us, is most evident towards the end of normal sleep, culminating in fREMP which, it is argued, is a proxy for ensuing wakefulness, especially with respect to behaviours oriented towards feeding. Moreover, this fREMP happens to coincide with our night sleep typically having developed into a fasting state and, to this extent, fREMP may well have important roles with: food preferences (and associated emotions), ‘nutrigenomics’, anti-obesity mechanisms, ‘overeating’/positive energy balance and obesity in short sleepers (absent final REM period), and variable weight gains with REM suppressant antidepressants. Finally, such a perspective also encourages a more ‘ecological’ approach to REM that would not be so readily apparent within laboratory settings.

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13 REFERENCES 1.Horne JA. Why REM sleep ? Clues beyond the laboratory in a more challenging world. Biol Psychol 2013; 92 ;152-168. 2. Horne JA. REM sleep, energy balance , optimal foraging. Neurosci Biobehav Rev 2009; 33: 466-474 3. Jepma M, Verdonschot RG, van Steenbergen H, Rombouts SA, Nieuwenhuis S. Neural mechanisms underlying the induction and relief of perceptual curiosity. Front Behav Neurosci 2012; 6: 5. 4. Jauch-Chara K, Oltmanns KM. Obesity - A neuropsychological disease? Systematic review and neuropsychological model. Prog Neurobiol. 2014; 114C: 84-101. 5. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature. 2006; 441: 589-94 6. Fuller PM, Saper CB, Lu J. The pontine REM switch: past and present. J Physiol 2007; 584: 735-41 7. Luppi PH, Clément O, Fort P. Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control. Curr Opin Neurobiol 2013; 23: 786-92 8. Solms M. New findings on the neurological organisation of dreaming, implications for psychoanalysis. Psychoanalytic Quart 1995; 64: 43-67. 9. Dang-Vu TT, Schabus M, Desseilles M, Sterpenich V, Bonjea M, Maquet P.unctional neuroimaging insights into the physiology of human sleep. Sleep 2010; 33:1589-603 10. Peigneux P, Laureys S, Fuchs S, Delbeuck X, Dequeldre C, Aert J, Delfiore G, Luxen A, Maquet P. Generation of rapid eye movements during paradoxical sleep in humans. Neuroimage 2001; 14: 701-708. 11. Miyauchi S, Misaki M, Kan S, Fukunaga T, Koike Y. Human brain activity time-locked to rapid eye movements during REM sleep. Exper Brain Res 2009; 192: 657-67 12. Morrison AR. Relationships between phenomena of paradoxical sleep and their counterparts in wakefulness. Acta Neurobiol Exper (Warsaw) 1979; 29:, 567-83 13. Hong CC, Harris JC, Pearlson GD, Kim JS, Calhoun VD, Fallon JH, Golay X, Gillen JS, Simmonds DJ, van Zijl PC, Zee DS, Pekar JJ. fMRI evidence for multisensory recruitment associated with rapid eye movements during sleep. Hum Brain Map 2009; 30:1705-22. 14. Kempermann G, Fabel K, Ehninger D, Babu H, Leal-Galicia P, Garthe A, Wolf SA. Why and how physical activity promotes experience-induced brain plasticity. Front Neurosci 2010; 4:Article 189. 15. Tobler I, Borbély AA. The effect of 3h and 6h sleep deprivation on sleep and EEG spectra of the rat. Behavior and Brain Research 1990; 36: 73-78 16. Rampin C, Cespuglio R, Chastrette N, Jouvet M. Immobilisation stress induces a paradoxical sleep rebound in the rat. Neuroscience Letters 1991;126:113-118.

Page 13 of 20

14 17. Oniani TN, Lortkipanidze ND, Mgaloblishivili M. Neurophysiological analysis of paradoxical sleep deprivation. In T. Oniani (Ed) Neurobiology of Sleep-wakefulness Cycle,Tibilisi , Metsniereba. 1998; Pp19-42. 18. Noakes TD, Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, Alkadhi K. The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Disease. 2012; 45:1153-62 19. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G , Sun YE., DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003; 302: 890-93 20. Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004; 20: 2580-90. 21. Lista I, Sorrentino G. Biological mechanisms of physical activity in preventing cognitive decline. Cellular Mol. Neurobiol. 2010; 230: 493-503. 22. Noble EE, Billington CJ, Kotz CM, Wang C. The lighter side of BDNF. Am J Physiol Regul Integr Comp Physiol 2011; 300: R1053-69 23. O’Keefe J, Nadel L.The Hippocampus as a Cognitive Map. 1978 Oxford University Press 24. Wilson MA, McNaughton BL. Dynamics of the hippocampal ensemble code for space. Science, 1993; 261:1055-8 25. Albasser MM, Dumont JR, Amin E, Holmes JD, Horne MR, Pearce JM, Aggleton JP. Association rules for rat spatial learning: The importance of the hippocampus for binding item identity with item location. Hippocampus 2013; 23:1162-78. 26. Quattrochi J, Datta S, Hobson JA. 1998 Cholinergic and non-cholinergic afferents of the caudo-lateral parabrachial nucleus: a role in the long-term enhancement of rapid eye movement sleep Neurosci. 1998; 83:1123-36. 27. Wu Q, Clark MS, Palmiter RD. Deciphering a neuronal circuit that mediates appetite. Nature. 2012; 483: 594-7 28. Carter ME, Soden ME, Zweifel LS, Palmiter RD. Genetic identification of a neural circuit that suppresses appetite. Nature. 2013; 503: 111-4 29. Li F, Li M, Cao W, Xu Y, Luo Y, Zhong X, Zhang J, Dai R, Zhou XF, Li Z, Li, C. Anterior cingulate cortical lesion attenuates food foraging in rats. Brain Res Bull 2012; 88: 602-8. 30. Hayes AL, Xu F, Babineau D, Patel SR. Sleep duration and circulating adipokine levels. Sleep 2011; 34:147-52 31. Torterolo P, Lagos P, Mont, JM. Melanin-concentrating hormone, a new sleep factor? Front Neurol 2011; 18: 2-14 32. Monti JM, Torterolo P, Lagos PM. Melanin-concentrating hormone control of sleep-wake behavior. Sleep Med Rev 2013; 17: 293-8. 33. Jego S, Salvert D, Renouard L., Mori M, Goutagny R, Luppi PH, Fort, P. 2012 Tuberal hypothalamic neurons secreting the satiety molecule Nesfatin-1 are critically involved in paradoxical (REM) sleep homeostasis. PLoS One 2012; 7: e52525.

Page 14 of 20

15 34. Jego S, Glasgow SD, Gutierrez-Herrera C, Ekstrand M, Reed SJ, Boyce R, Friedman J, Burdakov D, Adamantidis AR. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nature Neurosci 2013; 16:1637-43 34. Stengel A, More M, Taché Y. The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavours Obesity Rev 2013; 14: 59-70 35. Vas S, Ádori C, Könczöl K, Kátai Z, Pap D, Papp RS, Bagdy G, Palkovits M, Tóth ZE. Nesfatin-1/NUCB2 as a potential new element of sleep regulation in rats. PLoS One 2013; 8:e59809 36. Méndez-Díaz M, Domínguez Martín E, Pérez Morales M, Ruiz-Contreras AE, Navarro L, Prospéro-García O. The anorexigenic peptide cocaine-and-amphetamine-regulated transcript modulates rem-sleep in rats. Neuropeptides. 2009; 43:499-505. 37. Alexandre C, Andermann ML, Scammell TE. Control of arousal by the orexin neurons. Current Opin Neurobiol 2013; 23:752-9 38. Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005; 46: 787-798. 39. Rodgers NJ, Ishii Y, Halford JC, Blundell JE. Orexins appetite regulation. Neuropeptides 2002; 36: 303-325. 40. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Ann Rev Neurosci 2001; 24: 29-58 41. Shechter A, O'Keeffe M, Roberts AL, Zammit GK, RoyChoudhury A. St-Onge, MP. Alterations in sleep architecture in response to experimental sleep curtailment are associated with signs of positive energy balance. Am J Physiol - Reg Integ Comp Physiol.2012; 303:R883-9. 42. Gonnissen HK, Hursel R, Rutters F, Martens EA, Westerterp-Plantenga, MS. Effects of sleep fragmentation on appetite and related hormone concentrations over 24 h in healthy men. Br J Nutr 2012; 8:1-9 epub 43. Barbato G, Barker C, Bende C, Wehr TA. Spontaneous sleep interruptions during extended nights. Relat-ionships with NREM and REM sleep phases, effects on REM sleep regulation. Clin Neurophysiol 2002; 113: 892-900. 44. Kleitman N. Sleep and Wakefulness. 1966 Chicago : University Press 45. Saper CB, Fuller PM. Inducible clocks: living in an unpredictable world. Cold Spring Harbour Symposium – Quantitative Biology, 2007; 72: 543-550. 46. Mistleberger RE, Skene D. Nonphotic entrainment in humans? J Biol Rhythm 2005; 20: 339-52. 47. Antle MC, Silver R.Neural basis of timing and anticipatory behaviors. Euro J Neurosci 2009; 30:1643-9 48. Mistlberger RE, Antle M.Entrainment of circadian clocks in mammals by arousal and food. Essays Biochem 2011; 49:119-36

Page 15 of 20

16 49. Ootsuka Y, de Menezes RC, Zaretsky DV, Alimoradian A, Hunt J, Stefanidis A, Oldfield BJ, Blessing WW. Brown adipose tissue thermogenesis heats brain and body as part of the brain-coordinated ultradian basic rest-activity cycle. Neurosci. 2009; 164:849-61 50. Blessing W, Mohammed M, Ootsuka Y. Heating and eating: brown adipose tissue thermogenesis precedes food ingestion as part of the ultradian basic rest-activity cycle in rats. Physiol Behav 2012; 105: 966-74 51. Parmeggiani P-L.REM sleep related increase in brain temperature: a physiologic problem. Arch Ital Biol.2007; 145: 1321. 52. Horne JA. Why We Sleep. 1988 Oxford: University Press 53. Heller HC. Temperature, thermoregulation and sleep. In: MH Kryger, T Roth, WC. Dement (eds), Principles and Practice of Sleep Medicine, Philadelphia - Elsvier-Saunders, 2005, Pp292-304 54. Rosenthal MS, Vogel GW. The effect of a 3-day increase of ambient temperature toward thermoneutral zone on rapid eye movement sleep in the rat. Sleep 1993; 16: 702-705. 55. Schneider JE, Wise JD, Benton NA, Brozek JM, Keen-Rhinehart E. When do we eat? Ingestive behavior, survival, and reproductive success. Horm Behav 2013; 64:02-28. 56. Kotz C, Nixon J, Butterick T, Perez-Leighton C, Teske J, Billington, C. Brain orexin promotes obesity resistance. Annals of hte N Y Acad Sci 2012; 64: 72-86. 57. Sellayah D, Sikder D. Feeding the heat on brown fat Ann N Y Acad Sci. 2013; 1302:11-23. 58. Teske JA, Billington CJ, Kotz CM. Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neurosci. 2014; 3: 256:91-100 59. Fontvieille AM, Rising R, Spraul M, Larson DE, Ravussin E. Relationship between sleep stages and metabolic rate in humans. Am J Physiol 1994; 267: E732-7. 60. Siegel JM. Sleep viewed as a state of adaptive inactivity. Nature Rev Neurosci 2009; 10:747-53 61. Lyamin OI, Manger PR, Ridgway SH, Mukhametov LM, Siegel JM. Cetacean sleep: an unusual form of mammalian sleep. Neurosci Biobehav Rev 2008; 32: 1451-84. 62. Morrison AR, Sanford LD, Ross RJ. The amygdala, a critical modulator of sensory influence on sleep. Biol Sig Recept 2000; 9: 283-96 63. Bickart KC, Wright CI, Dautoff RJ, Dickerson BC, Barrett LF. Amygdala volume and social network size in humans. Nature Neurosci 2011; 14:163-164 64. Jacobs RAH, Renken R, Aleman A, Cornelissen FW. The amygdala, top-down effects, and selective attention to features. Neurosci Biobehav Rev 2012; 36:2069-84

Page 16 of 20

17 65. Nofzinger EA, Mintun MA, Wiseman M, Kupfer DJ, Moore RY. Forebrain activation in REM sleep: an FDG PET study. Brain Res.1997; 770:192-201 66. Cantero JL, Atienza M, Madsen JR, Stickgold R. Gamma EEG dynamics in neocortex and hippocampus during human wakefulness and sleep. Neuroimage 2004; 22:1271-1280 67. Nishida M, Uchida S, Hirai N, Miwakeichi F, Maehara T, Kawai K, Shimizu H, Kato S. High frequency activities in the human orbitofrontal cortex in sleep-wake cycle. Neurosci Lett. 2005; 379: 110-113 68.Vandekerckhove M, Cluydts R. The emotional brain and sleep: an intimate relationship Sleep Med Rev 2010; 14: 21926. 69. Rasch B, Born J. About sleep's role in memory. Physiol Rev 2013; 93: 681-766 70. Van der Helm E, Yao J, Dutt S, Rao V, Saletin JM, Walker MP. REM sleep depotentiates amygdala activity to previous emotional experiences. Curr Biol 2011; 21: 2029-32. 71. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. learning in humans: role of the amygdala and vmPFC. Neuron 2004; 43: 897-905. 72. Winecoff A, Clithero JA, Carter JM, Bergmann S, Wang L, Huettel S. Ventromedial prefrontal cortex encodes emotional value. J Neurosci. 2013; 33: 11032-39 73. Menz MM, Rihm JS, Salari N, Born J, Kalisch R, Pape HC, Marshall L, Büchel C. The role of sleep and sleep deprivation in consolidating fear memories. Neuroimage.2013; 75:87-96 74. Blagrove M, Fouquet NC, Henley-Einion JA, Pace-Schott EF, Davies AC, Neuschaffer JL, Turnbull OH. Assessing the dream-lag effect for REM and NREM stage 2 dreams. PLoS ONE 2011; 6: e26708 75. Perogamvros L, Dang-Vu TT, Desseilles M, Schwartz S. Sleep and dreaming are for important matters. Front Psychol. 2013; 4:474 76. Steenland HW, Li XY, Zhuo M.Predicting aversive events and terminating fear in the mouse anterior cingulate cortex during trace fear conditioning. J Neurosci.2012; 32:1082-95. 77. Nishida M, Hirai N, Miwakeichi F, Maehara T, Kawai K, Shimizu H, Uchida S. Theta oscillation in the human anterior cingulate cortex during all-night sleep: an electrocorticographic study.Neurosci Res. 2004; 50:331-41 78. Sheth SA, Mian MK, Patel SR, Asaad WF, Williams ZM, Dougherty DD, Bush G, Eskandar EN. Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation. Nature 2012; 488: 218-21 78. Suchecki D, Tiba PA, Machado RB. REM Sleep rebound as an adaptive response to stressful situations. Front Neurol.2012; 3:41. 79. Kolling N, Behrens TE, Mars RB, Rushworth MF. 2012. Neural mechanisms of foraging. Science. 2012; 336: 95-8.

Page 17 of 20

18 80. Gompf HS, Mathai C, Fuller PM , Wood DA, Pedersen NP, Saper CB, Lu J. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci 2010; 30: 4543-51 81. Bush G, Luu P, Posner M. Cognitive and emotional influences in anterior cingulated cortex. Trends Cog Sci 2000; 4: 215-222 82. Allman JM, Hakeem A, Erwin JM, Nimchinsky E, Hof P. The anterior cingulated cortex – the evolution of an interface between cognition and emotion. Ann NY Acad Sci 2001; 935: 107–17 83. Orr JM, Weissman DH.Anterior cingulate cortex makes two contributions to minimising distraction. Cerebral Cortex 2009; 19: 703-711 84. Hayden BY, Pearson JM, Platt ML. Neuronal basis of sequential foraging decisions in a patchy environment. Nature Neurosci 2011; 14: 933-9 85. Nachev P, Rees G, Parton A, Kennard C, Husain M. Volition and conflict in human medial frontal cortex. Curr Biol. 2005; 15: 122-8 86. Spoormaker VI, Gvozdanovic GA, Sämann PG, Czisch M. 2014 Ventromedial prefrontal cortex activity and rapid eye movement sleep are associated with subsequent fear expression in human subjects. Exp Brain Res. 2014; 23. [Epub ahead of print] 87. Suchecki D, Tiba PA, Machado RB. 2012 REM Sleep rebound as an adaptive response to stressful situations. Front Neurol. 2012; 3:41. 88. Datta S, O'Malley MW. Fear extinction memory consolidation requires potentiation of pontine-wave activity during REM sleep.Journal of Neuroscience 2013; 33:4561-9 89. Van Luijtelaar EL, Coenen AM. 1983, Differential behavioural effects of two instrumental paradoxical sleep deprivation techniques in rats. Biol Psychol 1983; 15: 85-93 90. Spoormaker VI, Schröter MS, Andrade KC, Dresler M, Kiem SA, Goya-Maldonado R, Wetter TC, Holsboer F, Sämann PG, Czisch M. Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signalling Hum Brain Map. 2011; 33: 362-76. 91. Siegel JM. REM sleep predicts subsequent food intake. Physiol Behav 1975;15: 399-403. 92. Bowersox SS, Baker TL, Demen, WC. Rapid eye movement sleep and its relationship to feeding behaviour in the adult cat. Physiol Behav 1984; 32: 907-90 93. Leproult R, Van Cauter E. Role of sleep and sleep loss in hormonal release and metabolism. Endocrinol Devel. 2010; 17:11-21. 94. Horne JA. Short sleep is a questionable risk factor for obesity and related disorders, statistical versus clinical significance. Biol Psychol 2008; 77: 266-276. 95. Horne JA. Obesity and short sleep – unlikely bed-fellows ? Obesity Rev 2011; 12: e84-94. Page 18 of 20

19 96. Klingenberg L, Sjödin A, Holmbäck U, Astrup A, Chaput J-P. Short sleep duration and its association with energy metabolism. Obesity Rev. 2012; 13: 565-577. 97. Cizza G, Requena M, Galli G, de Jonge L. Chronic sleep deprivation and seasonality: implications for the obesity epidemic J Endocr Investig. 2011; 34: 793-800 98. Calvin AD, Carter RE, Adachi T, Macedo PG, Albuquerque FN, van der Walt C, Bukartyk J, Davison DE, Levine, JA, Somers VKEffects of experimental sleep restriction on caloric intake and activity energy expenditure. Chest. 2013; 144:7986. 99. Markwald RR, Melanson EL, Smith MR, Higgins J, Perreault L, Eckel RH, Wright KP Jr. Impact of insufficient sleep on total daily energy expenditure, food intake, and weight gain. Proc Nat Acad Sci U S A. 2013; 110: 695-700. 100. Liu X, Forbes EE, Ryan ND, Rofey D, Hannon TS, Dahl RE. Rapid eye movement sleep in relation to overweight in children and adolescents Arch Gen Psychiat. 2008; 65: 924-32. 101. Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron 2011; 69:664-79 102. Mathers JC, Strathdee G, Relton CL. Induction of epigenetic alterations by dietary and other environmental factors Adv Genet. 2010; 71: 3-39 103. Jouvet M, Paradoxical sleep, is it the guardian of psychological individualism ? Can J Psychol 1991; 45:148-68. 104. Benedict C, Kern W, Schmid SM, Schultes B, Born J, Hallschmid M. Early morning rise in hypothalamic-pituitaryadrenal activity: a role for maintaining the brain's energy balance.Psychoneuroendocrinol 2009; 34:55-62. 105. Porter JM, Horne JA. Bed-time food supplements and sleep: effects of different carbohydrate levels.Electroenceph Clin Neurophysiol.1981; 51: 26-33. 106. Göder R, Seeck-Hirschner M, Stingele K, Huchzermeier C, Kropp C, Palaschewski M, Aldenhoff J, Koch J. Sleep and cognition at baseline and the effects of REM sleep diminution after 1 week of antidepressive treatment in patients with depression. J Sleep Res 2011; 20: 544-51. 107. Landolt HP, de Boer LP. Effect of chronic phenelzine treatment on REM sleep, report of three patients. Neuropsychopharm 2011; 25: S63-S67 108. Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. Human Psychopharm. 2005; 20: 533-59. 109. Wilson S, Argyropoulos S. Antidepressants and sleep, a qualitative review of the literature. Drugs 2005; 65:927-947. 110. MacFayden UM, Oswald I , Lewis SA. Starvation and human slow-wave sleep. J Appl Physiol. 1973; 35: 391-394. 111. Keys A, Brožek J, Henschel A, Mickelsen O, Taylor H L. The Biology of Human Starvation (2 volumes), 1950 University of Minnesota Press

Page 19 of 20

20 112. Lacey JH, Crisp AH, Kalucy RE, Hartmann MK , Chen CN. Weight gain and the sleeping electroencephalogram, study of 10 patients with anorexia nervosa. Br Med J . 1975; 4: 556-558 113. Poli F, Plazzi G, Di Dalmazi G, Ribichini D, Vicennati V, Pizza F, Mignot E, Montagna P, Pasquali R, Pagotto U. Body mass index-independent metabolic alterations in narcolepsy with cataplexy. Sleep 2009; 32:1491-7. 114. Buskova J, Klaschka J, Sonka K, Nevsimalova S. 0lfactory dysfunction in narcolepsy without catalepsy. Sleep Med. 2010; 11;558-61

Page 20 of 20