An evolutionary-emotional perspective of insomnia and parasomnias
Lampros Perogamvros a, b, c
a Center for Sleep Medicine, Department of Medical Specialties, Geneva University Hospitals,
Geneva, Switzerland b Department of Neuroscience, Faculty of Medicine, University of Geneva, Geneva,
Switzerland c Swiss Center for Affective Sciences, University of Geneva, Geneva, Switzerland
Corresponding author:
Lampros Perogamvros, MD
Department of Medical Specialties (Geneva University Hospitals) and Department of
Neuroscience (University of Geneva)
Chemin des Mines 9, 1202 Geneva, Switzerland [email protected]
1 Summary
Based on past literature, it is here supported that insomnia, and parasomnias such as sleepwalking, sleep terrors and nightmares, reflect an evolutionary survival mechanism, which has threat-related origins and which, in some vulnerable individuals, becomes persistent due to failure of a fear extinction function. Genetic determinants, personality traits and sleep disturbances seem to determine whether the individual will resume normal sleep after the acute phase (return to safety) or will develop the pathological condition of chronic insomnia, persistent sleepwalking in adulthood and nightmare disorder. Possible treatments targeting fear extinction are proposed, such as pharmacotherapy, cognitive behavioral therapy and targeted memory reactivation during sleep.
Keywords: insomnia, sleepwalking, nightmares, evolution, fear extinction
Abbreviations:
2 ACC: anterior cingulate cortex
CB1: cannabinoid receptor type 1
CBT : cognitive behavioral therapy
CBT-I: cognitive behavioral therapy for insomnia
CR: conditioned response
CS: conditioned stimulus
DSM5: Diagnostic and Statistical Manual of Mental Disorders- Fifth edition fMRI: functional magnetic resonance imaging
HEP: heartbeat evoked potential
ICSD3: International Classification of Sleep Disorders - Third Edition mPFC: medial prefrontal cortex
N2:stage 2 of NREM sleep
N3: stage 3 of NREM sleep
NREM: non-rapid eye movement sleep
PTSD: post-traumatic stress disorder
REM: rapid eye movement sleep
THC: tetrahydrocannabinol
TMR: targeted memory reactivation
TST: threat simulation theory
US: unconditioned stimulus
Introduction
3 The pathophysiology of insomnia and parasomnias remains poorly understood. The presence of an external or internal stressor has been associated with the appearance of acute insomnia
(1), nightmares (2), sleepwalking and sleep terrors (3). However, the factors accounting for the transition between the transient appearance of such disorders (usually few weeks) to a more persistent phase (usually many months or years) are not well understood. According to
DSM-5 (4), there are clear specifiers for the duration of insomnia disorder and nightmare disorder. For insomnia, the acute phase is defined as having a duration ≤1 month and the chronic phase, as persistence of insomnia for ≥3 months (4). For nightmares, the acute phase is defined as having a duration ≤1 month and the persistent phase, as the persistence of nightmares for ≥6 months (4). On the other hand, for disorders of arousal (NREM parasomnias), apart from the notion of recurrence of episodes, there are no clear duration specifiers in DSM-5 or ICSD-3. NREM parasomnias most often occur initially in childhood and decrease in occurrence until young adulthood. However, they may endure in adulthood, which characterizes a persistent form. The prevalence of chronic insomnia, persistent nightmares and adult sleepwalking is 10-20% (5) , 4% (6) and 2% (3), respectively.
Longitudinal or natural history studies are rather scarce in both insomnia (7) and parasomnia disorders (8), which could be of considerable help for understanding the nature of main determinants for the transition between transient and persistent phases of these disorders.
Genetic factors have been attributed to insomnia (9), sleepwalking (10) and nightmares (11).
Personality traits, which are largely genetically determined (12), have also been linked with insomnia (13), sleepwalking and nightmares (14). However, the specific role of genetic determinants, personality traits and stressful environmental events in the etiology of insomnia and NREM parasomnias is not yet clear.
4 Several theories have tried to explain how acute insomnia can develop into chronic insomnia
(15, 16). Most models support that behaviors and cognitions adopted by the individual to cope with acute insomnia, actually reinforce the problem and produce chronic insomnia, mainly by instrumental conditioning (17). A similar approach, of learned dysfunctional behaviors and cognitions, has also been followed for chronic nightmares (18). No such hypothesis has been given for sleepwalking or sleep terrors, perhaps because these disorders seem to decrease spontaneously in frequency and intensity during the transition between childhood and adulthood.
Recently, several different authors have suggested that the aforementioned sleep disorders may have served a survival function in our ancestral past (1, 19-21). At least for insomnia and sleepwalking, this function may have become unnecessary in post-industrial society, due to radical improvements in environmental safety. However, the threat-related origin of acute insomnia and parasomnias seems universal and intertemporal, although different in character between our ancestral past and the present. In this review, this idea of the evolutionary function of insomnia and parasomnias will be further developed, by proposing a common survival mechanism underlying the origin of these disorders. An adaptive response to real or perceived stress characterizes the transient phase of insomnia and parasomnias, whereas the failure of fear extinction and of return to safety would account for their persistent phase.
Specific factors would determine which individuals would return to normal sleep and who would develop a chronic sleep disorder. According to this perspective, targeting dysfunctional fear memories would be important for a successful treatment of these sleep disorders.
The evolutionary function of insomnias and parasomnias
5 According to the evolutionary mismatch hypothesis, specific traits that were once advantageous for human survival, became maladaptive due to changes in the environment
(22). In the following paragraphs, a mismatch hypothesis will be formulated for insomnia and parasomnias. It will be supported that insomnias and most parasomnias reflect an adaptive response to real or perceived stress, and that an evolutionary mismatch rendered these disorders rather dysfunctional in modern society (as compared to our ancestral past). Threat- related experiences seem to be at the origin of the acute forms of these phenomena in both the distant past and present of human history, while failure to extinguish the real or perceived threat would account, at least partly, for their persistence over time.
The evolutionary function of insomnia
Several authors have implied that acute insomnia is part of the normal stress response while encountering a danger in the environment. Spielman and Glovinsky state “No matter how important sleep may be, it was adaptively deferred when the mountain lion entered the cave”(23). For McNamara and Auerbach, insomnia is also an adaptive response to a perceived or real threat (24). Similarly, Ellis et al. suggested that acute insomnia is a normal biopsychosocial response to a perceived or actual stressor (1). Empirical evidence for this hypothesis comes from a recent study in Hadza hunter-gatherers of Tanzania, which shows that a chronotype variation and the resulting asynchrony in activity levels allow one or more individuals to stay awake during the night, which may serve a need for survival and protection from environmental dangers (25). As in modern western societies, such a danger (from wild animals, hostile tribes etc) is not an issue anymore, individuals should normally have continuous sleep without any need for hypervigilance. However, in dangerous neighborhoods in developed or developing countries (26) or under war conditions in both Western and non-
6 Western countries, such a behavior is found commonly (27), and it seems to chronically characterize war veterans as well (28).
Further evidence for this adaptive function of insomnia comes from electroencephalographic and cognitive studies, demonstrating a neurophysiological (cortical) and cognitive hyperarousal in these subjects, with milder cognitive costs and sleepiness in insomnia, as compared to sleep deprivation (29), even in those cases associated with significant objective short sleep duration (30). Most stressors causing acute insomnia in modern society are very different in nature than in physical threats, thus making us question what the benefit of losing sleep for them is. Anxiety about an exam or after a marital separation can cause insomnia, but these conditions are hardly comparable to being vigilant for predators or dangers. According to the mismatch hypothesis, initially adaptive solutions from our ancestral past and their modern ‘homologues’, would automatically activate the same ‘fight or flight’ systems.
Interestingly, sleep duration correlates negatively with predation risk, foraging and social interactions (31), implying that ecology, and not functional benefits of sleep, is the primary driver of sleep duration (20). This could mean that insomnia, either acute or chronic, would still reflect an ecological pressure nowadays. In this perspective, acute insomnia would be a result of a natural process signaling to the person that he has something better to do than sleep
(for example, beware of predators in the case of our ancestors or common everyday stressors for the post-industrial human). According to this hypothesis, everyone is at risk for acute insomnia as long as insomnia represents an adaptive response to stress (i.e., a real or perceived threat prevents the inhibition of wakefulness).This idea is also found in the Cano-
Saper rodent model and the psychobiological inhibition model of insomnia (32).
7 Under the current evolutionary scope, sleep-maintenance insomnia and early morning awakening may have similar threat-related origins with sleep-onset insomnia. Many western and equatorial pre-industrial populations had a biphasic sleep pattern, with the presence of a
‘first sleep’, which was interrupted by some activity, followed by a ‘second sleep’ (33).
Similarly to sleep-onset insomnia, sleep-maintenance insomnia could be the result of this adaptive bimodal sleeping pattern. Indeed, external threats may occur any time of the night.
As the Australian anthropologist George B. Silberbauer reported about the G/wi hunter- gatherers of southern Africa (34): “A G/wi camp never has an uninterrupted night’s sleep.
There is always someone awake, adding wood to the household fire, eating a snack, listening to a strange noise in the bush, or keeping watch if dangerous animals are near. For this reason, the divisions of the night are almost as important as those of the day.” More research in current pre-industrial societies is needed to verify if segmented sleep was a universal phenomenon or not before the onset of the Industrial Revolution.
Although it can be debated whether acute insomnia maintains the adaptive function it used to have in the past, chronic insomnia seems to reflect a pathological process where hyperarousal becomes self-perpetuating (via conditioning), even in the absence of the initial danger signs.
In the frame of our current evolutionary-emotional hypothesis, this would be translated into a failure of fear extinction processes, with no decline in conditioned fear responses throughout time in certain vulnerable individuals (see later section).
Unihemispheric sleep and the evolutionary function of sleepwalking
Similarly to insomnia, sleepwalking seems to occur only in humans (35). This specificity may be explained by the fact that human sleep has undertaken the larger evolutionary changes
8 across species (20), and the initial survival mechanism has gone awry in modern society.
Sleepwalking was already described in ancient Greece and was a known phenomenon to
Hippocrates and Aristotle (36). Very little is known about the evolutionary origins, function and physiopathology of sleepwalking.
The co-existence of wakefulness and sleep characterizes unihemispheric sleep, a phenomenon where half of the brain is awake and the other half asleep, so that animals (usually birds and aquatic mammals) can monitor the environment for threats, even while asleep (37). This phenomenon has also been described in humans, although not in its full ‘half-wake/half- asleep’ form. The ‘first-night effect’, the presence of disturbed sleep in a novel environment during the first night is a universal phenomenon, which represents hypervigilance that may correspond to survival mechanisms, and it reflects an interhemispheric asymmetry in sleep depth. It has been found that one hemisphere is less-asleep during the first night and shows increased vigilance in response to deviant stimuli (night-watch) during sleep (38).
Recently, it has been suggested that sleepwalking also reflects a survival reflex similar to unihemispheric sleep (21), where a lower arousal threshold of local cortical networks during
NREM sleep in humans, such as the motor cortex, anterior cingulate cortex (ACC) and amygdala (reviewed in (3)) would increase the probability of survival, facilitating motor readiness upon a sudden awakening because of an external threat. Previously learned and novelty seeking behaviors (14), probably representing an acting-out of a simultaneous dreamlike mentation (39), seem to confirm a fight-or-flight phenomenology of most episodes
(40). However, the simultaneous increased sleep pressure in other cortical areas (frontal and parietal dorsolateral cortices) controlling rationality and executive functions (3) makes this survival mechanism practically dysfunctional nowadays. So even if primitive brain regions
9 involved in emotional response (in the limbic system) and complex motor activity (within the cortex and potentially in the subcortex) remain in ‘active’ states and ready for a ‘fight or flight’ response (3), a global sleep phenomenon in other ‘rational’ regions makes this survival mechanism dysregulated, contrary to the functional unihemispheric sleep in other animals or the first-night effect in humans. A similar hybrid state (part sleep and part wakefulness) has accounted for insomnia too, according to the neurobiological model of insomnia (41). This model proposes an awake-like activity in fronto-parietal cortices, thalamus and hypothalamus
(local wakefulness) during NREM sleep. Insomnia may thus occur globally (objective insomnia) or more locally (subjective insomnia, paradoxical insomnia) (41), similarly to sleep
(42).
Our assumption is that similarly to insomnia, acute sleepwalking may have been functional in our ancestral past. We know that a sudden stimulus, like touch or sound, or stress can trigger a sleepwalking episode. As motor and cingulate cortices have a lower arousal threshold in sleepwalkers than controls (43), we speculate that leaders of a group taking care of the group’s safety, would develop a ‘partial’ unihemispheric sleep especially under conditions of uncertainty for the group (high predation risk, immigration etc). This dissociative state would cause these individuals to be in motor readiness during sleep when a sound or other stimulus in the environment was perceived as alarming. The presence of the ‘classic’ form of unihemispheric sleep cannot be formally excluded in primitive man and it may have evolved progressively to sleepwalking and the ‘first-night’ effect, due to increase of environmental security with human evolution. However, at later periods of human history, sleepwalking would be an evolutionary mismatch, as radical improvements in environmental safety (threats are almost extinct during the night), would not offer any functional benefit to sleepwalking.
10 In modern society, the onset of sleepwalking has been less commonly associated causally to real or perceived stress than acute insomnia or nightmares have, even though stressful events are common triggers of subsequent sleepwalking episodes (3). We know at least two threat- related causes (separation anxiety and war-related trauma), that can be implicated in the pathophysiology of sleepwalking (44, 45). According to the current hypothesis, failure to extinguish these memories could account for the perpetuation of sleepwalking into a persistent sleep disorder in adulthood.
The evolutionary function of other NREM parasomnias
Confusional arousals, sleep terrors and sleepwalking belong in the spectrum of arousal disorders. Therefore, a similar evolutionary perspective can be taken for confusional arousals and sleep terrors, as for sleepwalking. A common neurophysiological mechanism for all three disorders (43, 46), with wake-sleep state dissociation supports this idea. It seems that both confusional arousals and sleep terrors may represent the result of a low arousal threshold and reflect a partial arousal in order to monitor the environment for dangers. Indeed, according to a recent theory, sleep terrors reflect helplessness in human infants and a response to the evolutionary-environmental mismatch that has resulted from changes in human sleeping behavior from co-sleeping to sleeping separately (47).
The evolutionary function of dreams and nightmares
11 The Threat Simulation Theory (TST) (19) postulates that the evolutionary function of dreaming is to allow a selective offline simulation of threatening events that would promote the development of threat-avoidance skills in waking life. Phenomenologically, it has been shown that being chased or attacked is the most typical dream theme around the world (48), what supports the universality of threatening experiences in dreams. Neurophysiologically, a threat simulation system, mainly subserved by an activated amygdala in REM sleep (49), would be responsible for behaviorally and perceptually realistic threatening experiences in a dream, and would lead to improved performance in real life situations. The study of dreams in traumatized populations who simulate threatening events in their dreams more often than non- traumatized populations (50), and the observation that REM sleep deprivation impairs threat avoidance responses in real life (51), support this theory. More recently, we tested 127 healthy participants and found that those with higher incidence of fear in their dreams showed reduced fMRI response to fear-eliciting stimuli in the insula, amygdala and midcingulate cortex, while awake. Consistent with better emotion regulation processes, the same participants also displayed increased medial prefrontal cortex (mPFC) activity (52). Of note, the mPFC exerts an inhibitory control on fear expression by decreasing amygdala output and has been associated with fear extinction learning (i.e., when a neutral conditioned stimulus that previously predicted an aversive unconditioned stimulus no longer does so, and the conditioned response subsequently decreases) (see later section). This pattern of results is consistent with the TST, which claims that dreaming might serve to simulate responses to threatening events in a totally secure environment and by doing so, it would help the individual to respond in an adapted and efficient way to dangerous real-life events.
Fear is the most frequently reported main emotion in nightmares and bad dreams (48).
Therefore, according to our findings (52), we would expect nightmare sufferers to
12 demonstrate increased emotion regulation while awake. Indeed, TST considers threatening dreams and nightmares to be functional regardless of affect intensity. Research supporting the theory includes dream content analyses showing that college students report frequent threatening dreams that are both severe and realistic (e.g., aggression, misfortune themes) and during which appropriate responses are enacted by the dreamer (53). Moreover, in a recent study we found that the heartbeat-evoked potential (HEP), which indexes emotional arousal and which has an increased amplitude in REM sleep in nightmare sufferers compared to controls, is negatively correlated with depression scores in nightmare disorder (54), pointing out a potential emotional functional role of nightmares. However, it seems that such a role is present only for less severe forms of nightmares (in terms of intensity, frequency or arousability), and would diminish or be abolished as nightmares become chronic, more severe and recurrent in nature (see later section).
Threat-related origins of insomnia, arousal disorders and nightmares in human history
Until now we have explored how three distinct sleep disorders, insomnia, arousal disorders
(NREM parasomnias) and nightmares (a REM parasomnia) may share common evolutionary origins: they offered increased fitness benefits for our ancestors at the presence of an external threat (e.g. defending oneself or the group against predators and hostile conspecifics or caring for offspring for the mothers). Upon the presence of a threat, acute insomnia would represent global hypervigilance, arousal disorders would reflect a partial hypervigilance, whereas nightmares would be associated with emotional arousal within sleep, in order to be better prepared to deal with the threat. Hyperarousal, either total (insomnia) or partial (parasomnias), harm avoidance, and sensitivity to external or internal stressors, seem to be a common denominator in all three conditions, both phenomenologically (staying awake in insomnia, 13 frequent arousals in sleepwalking and nightmares), and neurophysiologically (increased high frequencies in the frontal cortex in insomnia, lower arousal threshold in sleepwalking, higher emotional arousal in nightmares). Interestingly, a higher sympathetic activity, expressing motor readiness and ‘fight-or-flight’ responses, is found in both insomnia (55) and nightmares
(56).
What is the origin of threats causing the acute forms of insomnia and parasomnias?
Throughout human history, the nature of threats causing sleeplessness (acute insomnia) has considerably changed for human beings. In our ancestral past, threats were mainly real
(predators and hostile conspecifics), whereas now they can be either real (war, crime) or perceived (anxiety). In addition, in early childhood, the occurrence of frequent arousals, somnambulism and sleep terrors is strongly associated with separation anxiety of the child and insecure mother-child attachment (45). Such an insecure attachment decreases the child's ability to fall asleep alone and return to sleep if an arousal takes place without signalling it to the parents. The initial occurrence of sleepwalking, sleep terrors and nightmares has been also causally related to traumatic experiences, with or without concurrent post-traumatic stress disorder (PTSD) (44). We know that anxiety, stress or high levels of insecurity (sleeping in a new environment) increase the occurrence of parasomnia episodes in both children and adults, supporting that sleepwalking/sleep terrors constitute, along with insomnia and nightmares, a partial hyperarousal reflecting an ancient survival mechanism at work.
A phenomenological study (40) supports a fight-or-flight phenomenology of parasomnias, as it demonstrated that 70% of enacted dreams in sleepwalking and sleep terrors involved a threat (especially misfortunes and disasters), with the flight response being much more common than the fight one in these NREM parasomnias. On the other hand, nightmares are
14 mainly characterized by physical aggressions (57), with fight responses in almost 75% of subjects (40).
Failure of fear extinction as mechanism for the transition from acute to persistent forms of insomnia and parasomnias
If fear-related, fight-or-flight responses are in the origins of the acute forms of insomnia and parasomnias, their perpetuation or remission should also be related to the preservation or extinction of real or perceived threats respectively. Therefore an emotional-evolutional consideration of both insomnia and parasomnias would place fear extinction processes (and their deficit) at the core of the physiopathology of the transition between acute and persistent forms of insomnia and parasomnias.
Fear conditioning refers to the pairing of a previously neutral stimulus (conditioned stimulus-
CS) with an innately aversive reinforcer (e.g., shock or loud noise) (unconditioned stimulus-
US), a procedure which comes to elicit a conditioned fear response (CR). Fear conditioning is subserved by the lateral nucleus of the amygdala, which encodes the association between the
CS and the US, and via projections to the central nucleus of the amygdala, ACC and insula, controls the expression of the CR (see (58) for a review). On the other hand, fear extinction is defined as the gradual decrease of the CR, because the CS is presented without reinforcement from the US. During fear extinction, an inhibitory memory that opposes the expression of the original fear memory is formed (59), due to molecular changes within the basolateral amygdala. The new extinction memory later undergoes consolidation, subserved by the basolateral amygdala, mPFC, and the hippocampus. The retrieval of the extinction memory is
15 related to increased activity in the mPFC, which exerts an inhibitory control on fear expression by decreasing amygdala output (58).
The persistence of fear in the absence of any imminent threat is a hallmark of anxiety disorders. Impaired ability to acquire or retrieve extinction learning may underlie such pathological anxiety. Importantly a delay of fear extinction is also found in insomnia disorder
(60), whereas its failure seems to be the underlying mechanism of nightmare disorder (2).
Delayed fear extinction in insomnia disorder
During fear conditioning, patients with insomnia disorder demonstrated activity in the ACC and the anterior insula, regions which are typically related to the expression of conditioned fear (60). Moreover, poorer sleep quality was associated with greater activation of these regions. The authors support that insomnia patients may be demonstrating enhanced anticipation of an aversive event (threat) compared to controls (60). On the other hand, during the phase of extinction learning, while the controls activated the mPFC, which is implicated in extinction learning, the patients showed no significant activity in this region. Interestingly, during early extinction recall, the patients showed activation in regions related to both fear expression (amygdala, insula, ACC) and fear extinction (mPFC), pointing out the presence of delayed fear extinction in chronic insomnia (60).
A similar conclusion, of delayed resolution of emotional distress, comes from a study showing that insomnia patients have reduced overnight resolution of emotional distress due to restless REM sleep (61). Another recent study comparing insomnia patients to healthy controls also demonstrated a decreased functional connectivity between the amygdala, insula,
16 striatum and thalamus, and, at the same time, an increased functional connectivity between the amygdala, premotor cortex and sensorimotor cortex (62). As the amygdala is the main region implicated in fear conditioning processes, these results seem to further support dysfunctional fear processes in insomnia disorder.
The aforementioned results point out that individuals with chronic insomnia demonstrate stronger fear conditioning than controls and a delay in extinction learning. In the evolutionary-emotional frame of our current hypothesis, this would mean that after an initial stressor triggered an episode of acute insomnia in an individual, persistence of the perceived stress or delay of its extinction over time may account for the perpetuation of insomnia and its transition into a chronic form (>3 months according to DSM5)(4). Therefore, treatment for chronic insomnia should address this delayed fear extinction.
Failure of fear extinction in nightmare disorder
Compared to controls, chronic nightmare patients show decreased regional cerebral blood flow in the mPFC when awake (63) and impaired frontal inhibitory functions (64), supporting that extinction learning fails when fear in dreams is exaggerated, as in nightmares. This failure of extinction learning (2) has an unknown mechanism, however we hypothesize that over-activating the limbic system during nightmares, by recruiting the ACC (54) and the amygdala (2), in addition to the insula (52), and at the same time a probable inhibition of the mPFC, reflects such a failure.
Therefore, according to the evolutionary-emotional perspective of nightmares, bad dreams/nightmares are considered functional to the extent that these provide opportunities to
17 identify threatening situations that might be met in real life and to practice adaptive reactions to them. This would lead to a return to safety and resolution of nightmares. However, it seems that such a functional role is valid only for specific types of nightmares, those where learning is achieved and the dreamed scenario can be somehow applied in real life (problem-solving), leading to emotion depotentiation, fear extinction and return of safety. If such an emotional resolution does not take place, and original fear memories are not replaced by fear extinction memories, nightmares become chronic, more severe and recurrent in nature, ‘‘taking on a life of their own’’, and becoming a learned dysfunctional behaviour (18).
Sleepwalking, sleep terrors and extinction learning
In a recent study (14), we found that as compared to norms for healthy subjects, chronic sleepwalkers displayed significantly higher anticipatory worrying. Both sleepwalking and nightmare patients share some general anticipatory fear, which is intermittently exacerbated by social rejection. Further supporting this claim, Rosen et al. proposed that sleepwalking and sleep terrors might be the nocturnal expression of otherwise repressed anger feelings toward life events (eg, separation, divorce), which can also be translated into failure to successfully suppress basic negative emotions, such as fear and anger (65).
According to the proposed hypothesis, a real or perceived threat would account for the transient form of sleepwalking (fear memory), whereas its persistent form in adulthood would be related to a delay or failure of fear extinction. Indeed, an unresolved, unextinguished fear memory, such as separation anxiety, insecure attachment or trauma, could be at the origin of the persistent sleepwalking/sleep terrors in adults. A hyperactive amygdala (46) may account for the intense fear and violent behaviour in sleepwalking and may reflect a hyperactive fear response. However, an external or internal stressor is less relevant or more difficult to identify
18 in the aetiology of sleepwalking than in insomnia and nightmares. The role of phylogenetic memory (‘inner fear’) (66), which is related to the experiences of a species over the eons, and which is driven by natural selection on the cellular/molecular mechanisms of neural development, may be possible in the case of parasomnias. Such memory does not depend on postnatal experience, but on the interactions of a species with its environment over evolutionary time. This could be tested by future prospective studies investigating the interactions between environmental and genetic determinants of arousal disorders. Exploring the evolutionary origins and reasons for maintaining in human history a ‘dysregulated survival reflex’ (21) as found in arousal disorders, seems primordially important.
Vulnerable populations for the transition between acute and chronic insomnia and parasomnias
According to the current hypothesis, successful fear extinction would be responsible for the return to safety and, subsequently, to normal sleep patterns, whereas a delay or failure of fear extinction would mainly account for the transition between the acute and chronic forms of insomnia and parasomnias. Genetic determinants, personality traits and sleep disturbances allowing or disturbing the fear extinction function seem to determine whether the individual will resume normal sleep after the acute phase (return to safety) or will develop the pathological condition of chronic insomnia, sleepwalking and nightmare disorder respectively.
Vulnerability for chronic insomnia
19 The genetic studies of insomnia (9, 67) have been performed in patients with chronic insomnia. We do not know if these factors influence the development of acute or chronic insomnia or both, although our hypothesis supports mainly the latter. In other words, all individuals are at risk for acute insomnia, as this represents an adaptive response to stress, but only a part of this population will develop chronic insomnia. However, one preliminary study has shown that there are individuals more prone than others to develop acute insomnia in the face of precipitating factors (stress) (68), while another study found an attenuated caudate recruitment in patients with chronic insomnia, even after successful treatment (69). More genetic, neuroimaging and personality studies in both acute and chronic phases of insomnia and parasomnias are needed to clarify if the current findings on genetic, neurobiological and personality traits (13, 14, 67) characterize only the chronic phase or both the acute and chronic phases.
Genetic factors and personality traits in insomnia disorder
A considerable genetic component has been attributed to chronic insomnia with heritability ranging from 38 to 59% due to longitudinal twin studies (67). Genes expressed specifically in the striatal medium spiny neurons and hypothalamic neurons were associated with insomnia
(70). Interestingly, striatal medium spiny neurons and hypothalamic neurons have been implicated previously in the regulation of reward processing, defensive behavioral responses and in fear conditioning (71, 72). Therefore, genetic polymorphisms could directly alter extinction learning and account for vulnerability to chronic insomnia.
In terms of personality traits, insomnia patients have increased harm avoidance, as well as decreased novelty seeking and self-directedness compared to controls (13). Harm-avoidance is a personality trait characterized by excessive worrying and fearfulness, while low self-
20 directedness is associated with an external locus of control, where the outcome of events in one’s life is mainly influenced by external forces beyond one’s control (73). As personality traits are strongly heritable (almost 60%) (12), despite variable cultures and environments, it seems that the aforementioned traits, found in post-industrial patients with insomnia, may reflect the profile of an ancestral ‘hypervigilant’ man, who monitors the environment for threats (increased harm avoidance), while knowing that the origin of the threat (usually a dangerous animal) is external and beyond his control (low self-directedness). Such low coping mechanisms of chronic stress in these individuals would contribute in the perpetuation of fear memories and a delayed fear-extinction characterizing chronic insomnia (60).
Vulnerability for parasomnias
Genetic factors and personality traits in sleepwalking and nightmare disorder
Present data suggests a considerable role of genetic factors in parasomnias. The estimated proportion of genetic effects is between 37% (adults) and 44% (childhood) of the phenotypic variance in nightmare disorder (11). On the other hand, the proportion of total phenotypic variance attributed to genetic influences was 60% (childhood) and 36-80% (adult women-men respectively) in sleepwalking (10).
We recently found (14) that compared to controls, patients with nightmare disorder and sleepwalking scored higher in novelty seeking and in particular on the exploratory excitability/curiosity subscale, and lower on the self-directedness scale, suggesting a general increase in reward sensitivity and impulsivity. Furthermore, patients tended to worry about social separation persistently, as indicated by greater anticipatory worry and dependence on social attachment. According to Nielsen and Levin (2), these traits may interact with basic
21 extinction processes, especially one’s susceptibility to affect distress, which could amplify the emotional responses produced in nightmares. Affect distress, linked to ACC activity, is shaped by the emotional history of the individual (e.g., early adversity) but also by pain- related distress, social rejection, and difficulties with emotional expression (2). Therefore, apart from the hypervigilant state influenced by high anticipatory worry and low self- directedness (found also in insomnia), sleepwalkers would in addition demonstrate high novelty seeking and exploratory excitability, suggesting a general increase in reward sensitivity and impulsivity. Contrary to a person staying awake and monitoring the environment for threats, but without taking any action (insomnia), people with sleepwalking, would search for active solutions, by acting out fight-or-flight responses.
Sleep-dependent disturbances
It has been shown that sleep promotes consolidation in multiple memory systems (74) and it may facilitate neural processes responsible for memory consolidation (75). Several studies have also demonstrated that sleep strengthens and generalizes extinction learning (76). More specifically, fear extinction processes were associated with N2 (77), N3 (78) and REM sleep
(79). In the last study, it is demonstrated that REM sleep in particular, is causal to successful consolidation of dangerous and safety stimuli and reduces return of fear after extinction. The aforementioned studies point out that sleep disturbance in insomnia and parasomnias can disrupt these fear extinction processes, producing a closed loop where the more sleep is fragmented, the more extinction fails and the more insomnia and parasomnias persist over time.
22 According to the current perspective, a lack of genetic/personality vulnerability, also translated into better coping mechanisms, as well as lack of sleep disturbances, would be responsible for faster fear extinction, yielding a fast return to normal sleep. In Figure 1 we propose a mechanism of dysfunction for insomnia and parasomnias based on fear conditioning.
Figure 1. Schematic representation of the emotional processes producing acute insomnia/parasomnias and the transition from acute to chronic insomnia/parasomnias. Proposed treatments of chronic insomnia/parasomnias in the frame of the current evolutionary-emotional perspective
According to the suggested hypothesis, accelerating fear extinction and the return to safety would be the main objectives of a personalized and emotion-based treatment for insomnias and parasomnias. These treatments would include pharmacotherapy, cognitive-behavioral therapy and targeted memory reactivation during sleep. 23 Pharmacotherapy
Some medications have been used in the past in order to extinguish fear memories. D- cycloserine, an N-methyl-D-aspartate glutamate receptor partial agonist, facilitates extinction learning and enhances extinction-related brain activation (80). Valpoic acid, a histone deacetylase inhibitor, also enhances fear extinction and prevents new acquisition of fear conditioning (81), both in wakefulness and sleep (82). Studies testing for the efficacy of valpoic acid and D-cycloserine in insomnia and parasomnias are needed. On the other hand, prazosin, a a1-adrenergic receptor antagonist, and beta-blockers (e.g. propranolol), which are efficient in treating nightmares (83), have also been found to enhance fear extinction processes in rats (84) and humans (85) respectively, which may point out a possible mechanism for these drugs in nightmares and reinforce the failure extinction model of Nielsen and Levin (2). Cannabinoid receptor type 1 (CB1) receptor agonists, such as tetrahydrocannabinol (THC), accelerate extinction learning (86), and are known to improve sleep continuity and to reduce sleep latency (87). Finally, a recent animal study showed that melatonin facilitates the extinction of conditional cued fear (88). Besides, melatonin seems to increase REM duration (89) and its chronic use may successfully treat chronic insomnia (90).
Therefore, both the sopoforic effects of CB1 agonists and melatonin and their effects on fear extinction (including sleep-dependent ones) could be used as an efficient treatment of chronic insomnia. Interestingly melatonin has also been used across different arousal disorders
(sleepwalking, sleep terrors) (3), which is in line with some common mechanisms across insomnia and parasomnias.
Cognitive behavioral therapy (CBT) 24 Under the scope of the current emotional model of insomnia/parasomnias, CBT should be in the center of the management of insomnia and parasomnias, as fear extinction has been considered the main psychophysiological mechanism behind this therapy, especially exposure therapy (91). Fear-related memories have both a cognitive and an emotional component. The cognitive component, which largely depends on the hippocampus, is associated with the precise context and details of the fear experience. The emotional component is related to physiological/ behavioral responses to danger, in the presence of learned predictors of danger.
Within this perspective, searching for and working with both the cognitive and emotional- behavioral aspects of the original fear memory would be crucial in order to alleviate symptoms of chronic insomnia and parasomnias. However, this is not always evident, especially for parasomnias, where such a postnatal stressor is usually difficult to identify or maybe even of phylogenetic origin. Importantly, more phenomenological studies of parasomnias are needed (40), in order to identify and work with specific fear memories in
CBT. On the other hand, a single fear memory may not be responsible for the maintenance of chronic insomnia. Both cued and contextual fear conditioning components have to be addressed for an efficient emotion-based cognitive-behavioral treatment of insomnia. Two examples of threat-related origins of insomnia and parasomnias are shown in Table 1.
A case of sleep terrors and sleepwalking
A 36-year-old female patient has had long-time sleep terrors and sleepwalking episodes since the age of 6 years old, with a frequency of 3 episodes per week. She has anxious, perfectionist and rational traits of personality. She lives in a mountain village. During the past summer, and while she was on holiday with a camper, she heard on the radio a significant weather advisory
25 of heavy thunderstorm and risk of flash floods. The same night, and 30 minutes after falling asleep, she woke up because she thought the water had risen in the camper and she grabbed her son violently, while shouting for help. During the past fall, some rockfalls blocked the road accessing her village, so the residents of the village were stranded. During the first night after this event, she woke up screaming because she saw the roof collapsing and a hole was apparent in the wall. Likewise, if she watches a heist film in the evening, it is highly probable that an episode of sleep terror will take place during the night, because she thinks strangers are in her house.
A case of sleep-onset insomnia and parasomnias
A 34-year-old female patient has suffered from several sleep disorders since the age of 16.
She developed these symptoms when she was in a boarding school, in which she was sleeping
with a roommate. Since then, she has begun to have sleep-onset insomnia, sleep paralysis (1 time per week on average), sleep terrors (1 time per week on average) and nightmares (4 times per week). These problems occur especially if she sleeps alone. If this is the case, she spends on average 2 hours awake before falling asleep. During the first half of the night, when her boyfriend happens to return to the apartment, she wakes up suddenly in intense fear and sits on her bed screaming. Other times, she wakes up paralyzed, while thinking that burglars or ‘bad spirits’ are in her room. Her dreams may have several morbid themes (e.g. being killed by someone, falling from high altitude) and often lead to an awakening with palpitations. The presence of someone in the apartment and/or in the room reassures her and, if this is the case, she has significantly less difficulty in getting to sleep and has fewer parasomnia episodes. It has to be noted, that both the sister and father of the patient suffer
26 from sleep paralysis.
Table 1. Two cases of identifiable threat origins of insomnia and parasomnia episodes.
Targeted memory reactivation
Targeted memory reactivation (TMR) (92) is a technique used to modify (strengthen or weaken) memory formation through application of cues during sleep. TMR seems to be an efficient method to accelerate memory consolidation, as the networks recruited for encoding and consolidation of new information are spontaneously reactivated during sleep. In a TMR protocol, an olfactory or auditory cue is associated with a learning procedure during the day and then administered during sleep. In that way, a neuronal replay in memory networks is artificially triggered, a procedure which will usually strengthen memory consolidation. TMR has been shown to improve declarative and procedural memory consolidation in humans (93) and to result in a performance gain and memory enhancement of around 30%, as compared to wakefulness (94).
Importantly, it has been demonstrated that pairing a fear memory with an olfactory or auditory stimulus and applying the stimulus in sleep increases fear extinction in humans (78, 95).
Future studies using such TMR protocols in insomnia and parasomnias are highly encouraged, considering that the origin of fear memory is sufficiently identified in these disorders.
Strengths and limitations of the model
The current model may be supplementary to other models of insomnia/parasomnias. Notably, it takes into account the common evolutionary origins of these disorders, the role of emotional
27 processing in their pathophysiology, and it explains the transition from acute to chronic insomnia/parasomnias.
Some other models of insomnia have tried to explain this transition. The 3P model (15) and neurocognitive model (16) consider how behaviors and cognitions adopted by the individual to cope with acute insomnia, would actually reinforce the problem and produce chronic insomnia, by instrumental conditioning. On the other hand, the cognitive model (96) proposes that the transition from acute to chronic insomnia occurs when sleep-related worry makes patients selectively attend to sleep-related threats and the daytime consequences of insomnia.
The psychobiologic inhibition model (97) proposes that a shift of attention (from the stressor to the insomnia symptoms), the intention to sleep and the associated cognitive effort inhibit chronically sleep-related dearousal. However, no model takes into account the emotional component of the disorder or the role of classical (fear) conditioning in the pathophysiology of transition between acute and chronic insomnia. It has been suggested that if only instrumental factors would account for chronic insomnia, CBT for insomnia (CBT-I) would produce more than 50% of remission in the acute treatment phase (32). Moreover, no current model addresses whether acute and chronic insomnia are distinct entities or if they explain sufficiently mechanisms of all three forms of insomnia (initial, middle, late). Finally, current models do not explain if the same hyperarousal mechanism accounts for both acute and chronic insomnia. The current evolutionary-emotional perspective of insomnia, and specifically the delay of fear extinction, may explain many of these missing points.
Another strength of the model is that it supports the existence of strong links between insomnia, parasomnias and anxiety, as fear conditioning is central in the pathophysiology of anxiety disorders (98). Importantly, unlike other sleep disorders, such as sleep apneas, an
28 associated stress is a common determinant for the pathophysiology of both acute insomnia and parasomnias. Indeed, an external or internal stressor can trigger episodes of insomnia, sleepwalking, sleep terrors and nightmares, as previously mentioned. Interestingly, a common evolutionary origin of insomnia and parasomnias comes from an early study (99), which found a moderate association between parasomnias and insomnia (r = 0.42), which was mainly accounted for by genetic influences (87%). The genetic correlation between parasomnias and insomnia was moderate to strong (r = 0.61). In contrast, the nonshared environmental correlation was very small (r = 0.10). Although more similar studies are certainly needed, these findings point out to a possible common origin of insomnias and parasomnias.
On the other hand, fear conditioning is not and cannot be the one and only pathophysiological mechanism of these disorders, nor can a dysregulated extinction learning account exclusively for the transition to chronicity. Although stress is one of the most common triggers of these disorders, NREM parasomnias can be also related to other factors such as substances (e.g. alcohol, zolpidem) and sleep deprivation, although causal links between sleep deprivation and stress have been documented (100). In addition, both classical and operant conditioning seem implicated in chronic insomnia (32). Testing the hypotheses and predictions of the current perspective will require a) natural history and observational studies in both preindustrial societies (25, 101, 102) and modern developed or developing countries (in both safe and less safe neighborhoods), b) longitudinal studies attempting to determine the specific role of genetics, personality traits and stressful environmental events in the etiology of acute/chronic insomnia and parasomnias, c) studies using experimentally induced stress in the laboratory
(103), and d) treatment trials, in order to test if targeting specific fear memories alleviate the symptoms of these disorders.
29 Conclusions
In this comprehensive hypothesis-driven review, it is supported that insomnia and parasomnias, such as sleepwalking and nightmares, are a result of an evolutionary survival mechanism.The current perspective considers that these disorders share common evolutionary origins, and takes into account the role of emotional processing and individual factors in their pathophysiology. Moreover, it attempts to explain the transient form of insomnias and parasomnias, which is related to an adaptive stress response to a perceived or real threat, and a more persistent (pathological) form of these disorders, where a failure or delay of extinction learning accounts at least partly for their pathophysiology. Finally, it proposes potential specific treatments, such as targeted memory reactivation during sleep and cognitive- behavioral therapy, which should address specific fear memories. Future longitudinal and natural history studies of insomnia disorder and parasomnias would shed more light on the understanding of the pathophysiology of these disorders.
Conflicts of interest
The author does not have any conflicts of interest to disclose.
Acknowledgments
The author would like to thank Thanh Dang-Vu, Anna Castelnovo and Stephen Perrig for helpful discussions about this paper.
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