Sleep and Emotional Memory Processing

Abstract

Cognitive neuroscience continues to build meaningful connections between affective behavior and human brain function. Within the biological sciences, a similar renaissance has taken place, focusing on the role of sleep in various neurocognitive processes, and most recently, the interaction between sleep and emotional regulation. In this article, we survey an array of diverse findings across basic and clinical research domains, resulting in a convergent view of sleep-dependent emotional brain processing. Based on the unique neurobiology of sleep, we outline a model describing the overnight modulation of affective neural systems and the (re)processing of recent emotional experiences, both of which appear to redress the appropriate next-day reactivity of limbic and associated autonomic networks. Furthermore, a REM sleep hypothesis of emotional-memory processing is proposed, the implications of which may provide brain-based insights into the association between sleep abnormalities and the initiation and maintenance of mood disturbances.

Introduction

The ability of the human brain to generate, regulate and be guided by emotions represents a fundamental process governing not only our personal lives, but our mental health as well as our societal structure. The recent emergence of cognitive neuroscience has ushered in a new era of research connecting affective behavior with human brain function, and provided a systems-level view of emotional information processing, translationally bridging animal models of affective regulation and relevant clinical disorders^35,52.

Independent of this research area, a recent resurgence has also taken place within the basic sciences, focusing on the functional impact of sleep on neurocognitive processes⁷⁷. However, surprisingly less research attention has been given to the interaction between sleep and affective brain function. We say surprising considering the remarkable overlap between the known physiology of sleep, especially REM sleep, and the associated neurochemistry and network anatomy that modulate emotions, as well as the prominent co-occurrence of abnormal sleep (including REM sleep) in almost all affective psychiatric and mood disorders.

Despite the relative historical paucity of research, recent work has begun to describe a consistent and clarifying role for sleep in the selective modulation of emotional memory and affective regulation. In the following review, we provide a synthesis of these findings, describing an intimate relationship between sleep, emotional brain function and clinical mood disorders, and offer a tentative first theoretical framework that may account for these observed interactions.

Sleep

The sleep of mammalian species has been broadly classified into two distinct types; non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, with NREM sleep being further divided in primates and cats into 4 sub-stages (1–4) corresponding, in that order, to increasing depth of sleep⁵⁷. In humans, NREM and REM sleep alternate or “cycle” across the night in an ultradian pattern every 90 min (Figure 1). Although this NREM-REM cycle length remains largely stable across the night, the ratio of NREM to REM within each 90 min cycle changes, so that early in the night stages 3 and 4 of NREM dominate, while stage 2 NREM- and REM sleep prevail in the latter half of the night. Interestingly, the functional reasons for this organizing principal (deep NREM early in the night, stage 2 NREM and REM late in the night) remain unknown (Walker, 2009).

Figure 1.

The human sleep cycle. Across the night, NREM and REM sleep cycle every 90 min in an ultradian manner, while the ratio of NREM to REM sleep shifts. During the first half of the night, NREM stages 3 and 4 NREM (SWS) dominate, while stage 2 NREM and REM sleep prevail in the latter half of the night. EEG patterns also differ significantly between sleep stages, with electrical oscillations such as slow delta waves developing in SWS, K-complexes and sleep spindles occurring during stage 2 NREM, and theta waves seen during REM.

As NREM sleep progresses, electroencephalographic (EEG) activity begins to slow in frequency. Throughout stage-2 NREM, there is the presence of phasic electrical events including K-complexes (large electrical sharp waves in the EEG) and sleep spindles (short synchronized bursts of EEG electrical activity in the 11–15 Hz range)⁶². The deepest stages of NREM, stages 3 and 4, are often grouped together under the term “slow wave sleep” (SWS), reflecting the occurrence of low frequency waves (0.5–4 Hz), representing an expression of underlying mass cortical synchrony³. During REM sleep, however, EEG wave forms once again change in their composition, associated with oscillatory activity in the theta band range (4–7 Hz), together with higher frequency synchronous activity in the 30–80 Hz (“gamma”) range^39,63. Periodic bursts of rapid eye movement also take place, a defining characteristic of REM sleep, associated with the occurrence of phasic endogenous waveforms. These waveforms are expressed in, among other regions, the pons (P), lateral geniculate nuclei of the thalamus (G), and the occipital cortex (O), and as such, have been termed “PGO waves”¹³.

As the brain passes through these sleep stages, it also undergoes dramatic alterations in neurochemistry⁵⁸. In NREM sleep, subcortical cholinergic systems in the brainstem and forebrain become markedly less active^27,40 while firing rates of serotonergic Raphé neurons and noradrenergic locus coeruleus neurons are also reduced relative to waking levels^5,60. During REM sleep, both these aminergic populations are strongly inhibited while cholinergic systems become as or more active compared to wake^31,42, resulting in a brain state largely devoid of aminergic modulation and dominated by acetylcholine.

At a whole-brain systems level, neuroimaging techniques have revealed complex and dramatically different patterns of functional anatomy associated with NREM and REM sleep (for review, see⁴⁸. During NREM SWS, brainstem, thalamic, basal ganglia, prefrontal, and temporal lobe regions all appear to undergo reduced activity. However, during REM sleep, significant elevations in activity have been reported in the pontine tegmentum, thalamic nuclei, occipital cortex, mediobasal prefrontal lobes together with affect-related regions including the amygdala, hippocampus and anterior cingulate cortex (Figure 2). In contrast, the dorso-lateral prefrontal cortex, posterior cingulate, and parietal cortex appear least active in REM sleep.

Figure 2.

Regional brain activation during REM sleep (PET scan). The areas include: (a) the pons; (b) amygdala; (c) thalamus; (d) right parietal operculum and (e) anterior cingulate cortex. The z-value color scale indicates strength of activation. A z-value of 3.09 corresponds to a p-value of less than .001⁴¹.

Although this summary only begins to describe the range of neural processes that are affected by the brain’s daily transit through sleep states, it clearly demonstrates that sleep itself cannot be treated as a homogeneous entity, offering a range of distinct neurobiological mechanisms that can support numerous brain functions. In the following sections, we will examine the role of sleep, and specific stages of sleep, in the modulation of emotional memories and the regulation of affective reactivity, which culminate in a heuristic model of sleep-dependent emotional brain processing.

Sleep and Emotional Memory Processing

The impact of sleep has principally been characterized at two different stages of memory 1) before learning, in the initial formation (encoding) of new information, and 2) after learning, in the long-term solidification (consolidation) of new memories^43,76,77. We now consider each of these stages, and focus on reports involving affective learning.

Sleep and Affective Memory Encoding

The initial stage of memory formation can be strongly modulated by the elicitation of emotion at the time of learning⁵³. Emotionally arousing stimuli are consistently remembered better than neutral stimuli both in experimental laboratory studies and in real life accounts (Heuer and Reisberg 1990; Bradley et al. 1992; Buchanan and Lovallo 2001, Christianson, 1992); s¹. The adrenergic system appears to play a key role in orchestrating the enhancing effect of arousing emotion on memory at the initial moment of learning (and also during consolidation, discussed later). For example, Cahill and colleagues have demonstrated that administration of propanolol, a β-adrenoceptor antagonist, to participants before learning of emotional and neutral narrative texts blocks the memory enhancing effects elicited by arousal¹². Similarly, propranolol administration before the encoding of affectively arousing word stimuli will subvert the normal facilitation of emotional memory recall when tested shortly after⁶⁵. Interestingly, this autonomic enhancing effect on memory is not observed in patients with amygdala lesions, suggesting a role not only for a specific neurochemical system in affective learning, but also a particular brain region^2,10. Indeed, functional neuroimaging studies have since confirmed the critical role of the amygdala in facilitating emotional memory formation at the time of experience^11,18;^{14,18,24,32,59}.

These beneficial enhancing effects of emotion on the initial process of learning pertain to conditions when the brain has obtained adequate prior sleep. There is now considerable evidence that sleep loss prior to encoding can significantly but also selectively alter and impair the canonical profile of emotional memory enhancement. While early studies investigating the role of sleep-dependent memory in humans focused primarily on post-learning consolidation (see later sections), more recent data similarly support the need for adequate pre-learning sleep in the formation of new human episodic memories. Some of the first studies of sleep deprivation and memory encoding focused on neutral forms of learning, indicating that “temporal memory” (memory for when events occur) was significantly disrupted by a night of pre-training sleep deprivation^25,45; even when caffeine was administered to overcome non-specific effects of lower arousal.

More recent investigations have examined the importance of pre-training sleep for the formation of emotional and neutral memories⁷⁷. Subjects were either sleep deprived for 36 hr or allowed to sleep normally prior to a learning session composed of emotionally negative, positive and neutral words, with the efficiency of encoding subsequently tested following two recovery nights of sleep. Averaged across all memory categories, subjects who were sleep deprived demonstrated a 40% deficit in memory encoding, relative to subjects who had slept normally prior to learning (Figure 3a). However, when these data were separated into the three emotional categories (negative, positive or neutral), selective dissociations became apparent (Figure 3b). In subjects that had slept (control group), both positive and negative stimuli were associated with superior retention levels relative to the neutral condition, consistent with the notion that emotion facilitates memory encoding⁵³. In the sleep-deprived group, a severe encoding impairment was evident for neutral and especially positive emotional memories, exhibiting a significant 59% retention deficit, relative to the control condition. Most interesting was the relative resistance of negative emotional memory to sleep deprivation, showing a markedly smaller and non-significant impairment.

Figure 3.

Sleep deprivation and encoding of emotional and non-emotional declarative memory. Effects of 38 hr of total sleep deprivation on encoding of human declarative memory a) When combined across all emotional and non-emotional categories, b) When separated by emotional (positive and negative valence) and non-emotional (neutral valence) categories, demonstrating a significant group [sleep, sleep-deprivation] × emotion category [positive, negative, neutral] interaction (F(1,18) 3.58, p < .05). Post-hoc t-test comparisons:

†p < .08, *p < .05, **p < .01, n.s. not significant, error bars represent s.e.m. From Walker, M. P., & Stickgold, R. (2006). Sleep, memory, and plasticity. Annual Reviews in Psychology, 57, 139–166; Fig 2, p 144; with permission.

These data indicate that sleep loss impairs the ability to commit new experiences to memory, and has recently been associated with dysfunction throughout the hippocampal complex⁷⁹. They also suggest that, while the effects of sleep deprivation are directionally consistent across emotional sub-categories, the most profound impact is on the encoding of positive emotional stimuli, and to a lesser degree, emotionally neutral stimuli. In contrast, the encoding of negative memory appears to be more resistant to the effects of prior sleep loss. Moreover, such results may offer novel learning and memory insights into affective mood disorders that express co-occurring sleep abnormalities⁷, whereby sleep deprivation imposes a skewed distribution of learning, resulting in a dominance of negative memory representations.

Sleep and Affective Memory Consolidation

The role of sleep in declarative memory consolidation, rather than being absolute, may depend on more intricate aspects of the information being learned, such as novelty, meaning to extract, and also the affective salience of the material. A collection of findings have described a preferential offline consolidation benefit (reduction in forgetting) for emotional compared to neutral information. Furthermore, this differential emotional advantage appears to persist and even improve over time periods containing a night of sleep^{34,36,38,59,75}. Indeed, several reports have directly examined whether it is time, with sleep, that preferentially modulates these effects. Based on the coincident neurophysiology that REM sleep provides and the neurobiological requirements of emotional memory processing^9,44, work has now begun to test a selective REM sleep-dependent hypothesis of affective human memory consolidation.

For example, Hu et al. have compared the consolidation of emotionally arousing and non-arousing picture-stimuli following a 12 hr period across a day or following a night of sleep²⁹. A specific emotional memory benefit was observed only following sleep and not across an equivalent time awake. Atienza and Cantero have also demonstrated that total sleep deprivation the first night after learning significantly impairs later one-week retention of emotional as well as neutral visual stimuli⁶. Interestingly, this difference was greatest for neutral relative to emotional items. Such a difference may indicate that emotional items are more resistant to the impact of first night sleep deprivation (a finding with clinical treatment consequences), or that subsequent post-deprivation recovery sleep is more capable of salvaging consolidation of emotional relative to neutral memories. Wagner and colleagues⁷² have also shown that sleep selectively favours the retention of previously learned emotional texts relative to neutral texts, and that this affective memory benefit is only present following late-night sleep (a time period rich in REM sleep). This emotional memory benefit was found to persist in a follow-up study performed four years later⁷³. It has also been demonstrated that the speed of recognizing emotional face expressions presented prior to sleep is significantly improved the next day, a benefit that is positively correlated with the amount of intervening REM sleep⁷⁴.

Sleep has also been shown to target the consolidation of specific aspects of emotional experiences, as well as mediate the extinction of human fear memories. By experimentally varying the foreground and background elements of emotional picture stimuli, Payne et al. have demonstrated that sleep can target the strengthening of negative emotional objects in a scene, but not the peripheral background⁵¹. In contrast, equivalent time awake did not afford any selective benefit to emotional object memory (or the background scene). This may suggest that sleep-dependent processing can selectively separate episodic experience into component parts, preferentially consolidating those of greatest affective salience. Using a conditioning paradigm in humans, Pace-Schott and colleagues recently investigated the effects of sleep and wake on fear extinction and generalization of fear extinction (Pace-Schott, et al., 2009). Concurrent fear conditioning to two different stimuli was followed by targeted extinction of conditioned responding to only one of the stimuli. Participants were then tested following a 12hr offline delay period across the day or following a night of sleep. Upon returning 12hr later, generalization of extinction from the target stimuli to the non-targeted stimuli occurred following a night of sleep, yet not across an equivalent waking period. Therefore, sleep may not only modulate affective associations between stimuli, but additionally facilitate their generalization across related contexts.

Nishida et al. have demonstrated that sleep, and specifically REM sleep neurophysiology, may underlie such consolidation benefits⁴⁷. Subjects performed two study sessions in which they learned emotionally arousing negative and neutral picture stimuli; one 4 hr prior, and one 15 min prior to a recognition memory test. In one group, participants slept (90 min nap) after the first study session, while in the other group, participants remained awake. Thus, items from the first (4 hr) study sessions transitioned through different brain-states in each group prior to testing, containing sleep in the Nap group and no sleep in the No-Nap group, yet experienced identical brain-state conditions following the second study session, 15 min prior to testing. No change in memory for emotional (or neutral stimuli) occurred across the offline delay in the no-nap group. However, a significant and selective offline enhancement of emotional memory was observed in the nap group (Figure 4a), the extent of which was correlated with the amount of REM sleep (Figure 4b), and the speed of entry into REM sleep (latency; not shown in figure). Most striking, spectral analysis of the EEG demonstrated that the magnitude of right-dominant prefrontal theta power during REM sleep (activity in the frequency range of 4.0–7.0 Hz) exhibited a significant and positive relationship with the amount of emotional memory improvement (Figure 4c&d).

Figure 4.

REM sleep enhancement of negative emotional memories. a) Offline benefit (change in memory recall for 4 hr versus 15 min old memories) across the day (wake, grey bar) or following a 90 min nap (sleep, filled bar); b) Correlation between the amount of offline emotional memory improvement in the nap group (i.e. the offline benefit expressed in filled bar of figure a), and the amount of REM sleep obtained within the nap; c) Correlation strength (Pearson’s r-value) between offline benefit for emotional memory in the sleep group (the benefit expressed in filled bar of figure a) and the relative right versus left prefrontal spectral-band power ([F4 – F3]) within the delta, alpha, theta and beta spectral bands, expressed in average 0.5 Hz bin increments. Correlation strength is represented by the color range, demonstrating significant correlations within the theta frequency band (hot colors), and d) exhibiting a maximum significance at the 5.75 Hz bin.

*p < .05; error bars indicate s.e.m. (Modified from Nishida M, Pearsall J, Buckner RL, Walker MP (2009) REM sleep, prefrontal theta, and the consolidation of human emotional memory. Cereb Cortex 19:1158–1166.).

These findings move beyond demonstrating that affective memories are preferentially enhanced across periods of sleep, and indicate that the extent of emotional memory improvement is associated with specific REM sleep characteristics – both quantity and quality (and independent of nocturnal hormonal changes). Corroborating these correlations, it has previously been hypothesized that REM sleep represents a brain-state particularly amenable to emotional memory consolidation, based on its unique biology^29,50. Neurochemically, levels of limbic and forebrain ACh are markedly elevated during REM sleep⁷⁰, reportedly quadruple those seen during NREM and double those measured in quiet waking⁴². Considering the known importance of ACh in the long-term consolidation of emotional learning⁴⁴, this pro-cholinergic REM sleep state may promote the selective memory facilitation of affective memories, similar to that reported using experimental manipulations of ACh⁵⁵. Neurophysiologically, theta oscillations have been proposed as a carrier frequency, allowing disparate brain regions that initially encode information to selectively interact offline, in a coupled relationship. By doing so, REM sleep theta may afford the ability to strengthen distributed aspects of specific memory representations across related but different anatomical networks^8,30.

Sleep and Emotional Regulation

Relative to the interaction between sleep and affective memory, the impact of sleep loss on basic regulation and perception of emotions has received substantially less research attention. Nevertheless, a number of studies evaluating subjective as well as objective measures of mood and affect, offer an emerging experimental understanding for the critical role sleep plays in regulating emotional brain function, complimenting a rich associated clinical literature.

Sleep loss, mood stability and emotional brain (re)activity

Together with impairments of attention and alertness, sleep deprivation is commonly associated with increased subjective reports of irritability and affective volatility²⁸. Using a sleep restriction paradigm (5hr/night), Dinges et al. have reported a progressive increase in emotional disturbance across a one-week period on the basis of questionnaire mood scales¹⁷. In addition, subjective descriptions in participants’ daily journals also indicated increasing complaints of emotional difficulties. Zohar et al. have investigated the effects of sleep disruption on emotional reactivity to daytime work events in medical residents⁸⁰. Sleep loss was shown to amplify negative emotional consequences of disruptive daytime experiences while blunting the positive benefit associated with rewarding or goal-enhancing activities.

While these findings help to characterize the behavioral irregularities imposed by sleep loss, evidence for the role of sleep in regulating psychophysiological reactivity and emotional brain networks is only now starting to emerge. To date, only two studies have addressed this interaction. Using functional MRI (fMRI), Yoo and colleagues examined the impact of one night of sleep deprivation on emotional brain reactivity in healthy young adults⁷⁸. During scanning, participants performed an affective stimulus-viewing task involving the presentation of picture slides ranging in a gradient from emotionally neutral to increasingly negative and aversive. While both groups expressed significant amygdala activation in response to increasingly negative picture stimuli, those in the sleep-deprivation condition exhibited a remarkable +60% greater magnitude of amygdala reactivity, relative to the control group (Figure 5a&5b). In addition to this increased intensity of activation, there was also a marked increase in the extent of amygdala volume recruited in response to the aversive stimuli in the sleep-deprivation group (Figure 5b). Perhaps most interestingly, relative to the sleep-control group, those who were sleep deprived showed a significant loss of functional connectivity identified between the amygdala and the medial prefrontal cortex (mPFC) – a region known to have strong inhibitory projections to the amygdala⁶¹ (Figure 5c&5d). In contrast, significantly greater connectivity was observed between the amygdala and the autonomic-activating centers of the locus coeruleus in the deprivation group. Therefore, without sleep, an amplified hyper-limbic reaction by the human amygdala was observed in response to negative emotional stimuli, associated with a loss of top-down connectivity with the prefrontal lobe. Interestingly, a similar pattern of anatomical dysfunction has been implicated in a number of psychiatric mood disorders, which express co-occurring sleep abnormalities^15,16,46, and directly raises the issue of whether sleep loss plays a causal role in the initiation or maintenance of clinical mood disorders.

Figure 5.

The impact of sleep deprivation on emotional brain reactivity and functional connectivity. a) Amygdala response to increasingly negative emotional stimuli in the Sleep deprivation and Sleep control groups, and b) Corresponding differences in intensity and volumetric extent of amygdala activation between the two groups (average ± s.e.m. of left and right amygdala), c) Depiction of associated changes in functional connectivity between the medial prefrontal cortex (mPFC) and the amygdala. With sleep, the prefrontal lobe was strongly connected to the amygdala, regulating and exerting and inhibitory top-down control, d) Without sleep, however, amygdala-mPFC connectivity was decreased, potentially negating top-down control and resulting in an overactive amygdala.

*p < .01; error bars indicate s.e.m. (Modified from Yoo SS, Gujar N, Hu P, et al: The human emotional brain without sleep - a prefrontal amygdala disconnect. Curr Biol 17:R877, 2007⁷⁸; with permission.)

Complementing these findings, Franzen et al. have examined the impact of total sleep deprivation on pupil diameter responses (a measure of autonomic reactivity) during a passive affective picture-viewing task containing positive, negative and neutral stimuli²⁰. Relative to a sleep control group, there was a significantly larger pupillary response to negative pictures compared to positive or neutral stimuli in the deprivation group. Most recently, Gujar et al.²³ have compared the change in reactivity to specific types of emotions (Fear, Anger, Happiness, Sadness) across a 6hr daytime waking interval that either did or did not contain a 90 min nap. Without sleep, reactivity and intensity ratings towards threat-relevant negative emotions (Anger and Fear) significantly increased with continued time awake. However, an intervening nap blocked (Anger) and even reversed (Fear) these increases towards aversive stimuli, while conversely enhancing sensitivity toward reward-relevant happy facial expressions. Most interestingly, only those subjects in the nap group who obtained REM sleep displayed this resetting of affective reactivity.

A heuristic model of sleep-dependent emotional processing

Based on the emerging interaction between sleep and emotion, we next provide a synthesis of these findings, which converge on a functional role for sleep in affective brain modulation. We describe a model of sleep-dependent emotional information processing, offering provisional brain-based explanatory insights regarding the impact of sleep abnormalities in the initiation and maintenance of certain mood disorders, and leading to testable predictions for future experimental investigations.

The findings discussed above suggest a predisposition for the encoding of negative emotional memories and a hyper-limbic reactivity to negative emotional events under conditions of sleep loss, together with a strengthening of negative memories during subsequent REM sleep, all of which have potential relevance for the understanding of major depression. Thus, at both stages of early memory processing – encoding and consolidation – the architectural sleep abnormalities expressed in major depression may facilitate an adverse prevalence and strengthening of prior negative episodic memories. Yet, there may be an additional consequence of sleep-dependent memory processing, beyond the strengthening of the experience itself, and one that has additional implications for mood disorders – that is, sleeping to forget.

Emotional-memory processing: A sleep to forget and sleep to remember (SFSR) hypothesis

Founded on the emerging interaction between sleep and emotion, below we outline a model of affective information processing that may offer brain-based explanatory insights regarding the impact of sleep abnormalities, particularly REM sleep, on the initiation or maintenance of mood disturbance.

Although there is abundant evidence to suggest that emotional experiences persist in our autobiographies over time, an equally remarkable but less noted change is a reduction in the affective tone associated with their recall. The reason that affective experiences appear to be encoded and consolidated more robustly than neutral memories is due to autonomic neurochemical reactions elicited at the time of the experience⁴⁴, creating what we commonly term an “emotional-memory”. However, the later recall of these memories tends not to be associated with anywhere near the same magnitude of autonomic (re)activation as that elicited at the moment of experience – suggesting that, overtime, the affective “blanket” previously enveloping the memory during learning has been removed, whereas the information contained within that experience (the memory) remains.

For example, neuroimaging studies have shown that initial exposure and learning of emotional stimuli is associated with substantially greater activation in the amygdala and hippocampus, relative to neutral stimuli^18,19,33. In one of these studies¹⁸, however, when participants were re-exposed to these same stimuli during recognition testing many months later, a change in the profile of activation occurred¹⁹. Although the same magnitude of differential activity between emotional and neutral items was observed in the hippocampus, this was not true in the amygdala. Instead, the difference in amygdala (re)activity to emotional items compared with neutral items had dissipated over time. This would support the idea that the strength of the memory (hippocampal-associated activity) remains at later recollection, yet the associated emotional reactivity to these items (limbic network activity) is reduced over time.

This hypothesis predicts that such decoupling preferentially takes place overnight; such that we sleep to forget the emotional tone, yet sleep to remember tagged memory of that episode (SFSR model; Figure 6). The model further argues that if this process is not achieved, the magnitude of affective “charge” remaining within autobiographical memory networks would persist, resulting in the potential condition of chronic anxiety or PTSD.

Figure 6.

The sleep to forget and sleep to remember (SFSR) model of emotional memory processing: a) Neural dynamics. Waking formation of an episodic emotional memory involves the coordinated encoding of hippocampal-bound information within cortical modules, facilitated by the extended limbic system, including the amygdala, and modulated by high concentrations of aminergic neurochemistry. During subsequent REM sleep, these same neural structures are reactivated, the coordination of which is made possible by synchronous theta oscillations throughout these networks, supporting the ability to reprocess previously learned emotional experiences. However, this reactivation occurs in a neurochemical milieu devoid of aminergic modulation, and dominated by cholinergic neurochemistry. As a consequence, emotional memory reprocessing can achieve, on the one hand, a depotentiation of the affective tone initially associated with the event(s) at encoding, while on the other, a simultaneous and progressive neocortical consolidation of the information. The latter process of developing stronger cortico-cortical connections additionally supports integration into previous acquired autobiographical experiences, further aiding the assimilation of the affective event(s) in the context of past knowledge, the conscious expression of which may contribute to the experience of dreaming. Cross-connectivity between structures is represented by number and thickness of lines. Circles within cortical and hippocampal structures represent information nodes; shade reflects extent of connectivity: strong (filled), moderate (grey) and weak (clear). Fill of limbic system and arrow thickness represents magnitude of co-activation with and influence on the hippocampus. b) Conceptual outcome. Through multiple iterations of this REM mechanism across the night, and/or across multiple nights, the long-term consequence of such sleep-dependent reprocessing would allow for the strengthening and retention of salient information previously tagged as emotional at the time of learning. However, recall no longer maintains an affective, aminergic charge, allowing for post-sleep recollection with minimal autonomic reactivity (unlike encoding), thereby preventing a state of chronic anxiety.

Based on the unique neurobiology of REM, here we propose a REM sleep hypothesis of emotional brain processing (Figure 6a). We suggest that the state of REM provides an optimal biological theater, within which, can be achieved a form of affective “therapy”. Specifically, increased activity within limbic and paralimbic structures during REM sleep may first offer the ability for reactivation of previously acquired affective experiences. Second, the neurophysiological signature of REM sleep involving dominant theta oscillations within subcortical as well as cortical nodes may offer large-scale network cooperation at night, allowing the integration and, as a consequence, greater understanding of recently experienced emotional events in the context of pre-existing neocortically stored semantic memory. Third, these interactions during REM sleep (and perhaps through the conscious process of dreaming) critically and perhaps most importantly take place within a brain that is devoid of aminergic neurochemical concentration⁴⁹, particularly noradrenergic input from the locus coeruleus; the influence of which has been linked to states of high stress and anxiety disorders⁶⁷. Therefore, the neuroanatomical, neurophysiological and neurochemical conditions of REM sleep may offer a unique biological milieu in which to achieve, on one hand, a balanced neural facilitation of the informational core of emotional experiences (the memory), yet may also depotentiate and ultimately ameliorate the autonomic arousing charge originally acquired at the time of learning (the emotion), negating a long-term state of anxiety (Figure 6).

Specific predictions emerge from this model. First, if this process of divorcing emotion from memory were not achieved across the first night following such an experience, the model would predict that a repeat attempt of affective demodulation would occur on the second night, since the strength of the emotional “tag” associated with the memory would remain high. If this process failed a second time, the same events would continue to repeat across ensuing nights. It is just such a cycle of REM-sleep dreaming (nightmares) that represents a diagnostic key feature of post-traumatic stress disorder³⁷. It may not be coincidental, therefore, that these patients continue to display hyperarousal reactions to associated trauma cues^26,54, indicating that the process of separating the affective tone from the emotional experience has not been accomplished. The reason why such a REM mechanism may fail in PTSD remains unknown, although the exceptional magnitude of trauma-induced emotion at the time of learning may be so great that the system is incapable of initiating/completing one or both of these processes, leaving some patients unable to integrate and depotentiate the stored experience. Alternatively, it may be the hyperarousal status of the brain during REM sleep in these patients^26,54,66, potentially lacking sufficient aminergic demodulation, that prevents the processing and separation of emotion from memory. Indeed, this hypothesis has gained support from recent pharmacological studies in PTSD patients, demonstrating that nocturnal alpha-adrenergic blockade using prazosin (that is, reducing adrenergic activity during sleep) both decreases trauma-dream symptomatology and restores characteristics of REM sleep^56,68. This model also makes specific experimental predictions as to the fate of these two components – the memory and the emotion. As partially demonstrated, the first prediction would be that, overtime, the veracity of the memory itself would be maintained or improved, and the extent to which these [negative] emotional experiences are strengthened would be proportional to the amount of post-experience REM sleep obtained, as well as how quickly it is achieved (REM latency).

Second, using physiology measures, these same predictions would hold in the inverse direction for the magnitude of emotional reactivity induced at the time of recall. Together with the neuroimaging studies of emotional memory recall over time, and psychological studies investigating the role of REM sleep dreaming in mood regulation, a recent fMRI study offers perhaps the strongest preliminary support of this sleep-dependent model of emotional-memory processing⁶⁴. Relative to a control group that slept, participants who were deprived of sleep the first night after learning arousing emotion picture slides not only showed reduced recall of the information 72hr later (the sleep to remember component of the hypothesis), but also showed a lack of reduction in amygdala reactivity when re-exposed to these same negative emotional picture slides at recognition testing (Figure 7; the sleep to forget component of the hypothesis). Thus, sleep after learning facilitated improved recollection of these prior emotional experiences, yet this later recollection was conversely associated with a reduction in amygdala reactivity after three nights. In contrast, those who did not sleep the first night after the emotional learning session, despite obtaining two full recovery nights of sleep, exhibited no such depotentiation of subsequent amygdala reactivity.

Figure 7.

Impact of sleep deprivation on limbic brain activity during subsequent emotional memory retrieval. a) Higher degree of amygdala reactivity during delayed (72hr) recollection of previously learned negative emotion picture slides in participants that were sleep deprived the first night after learning, compared to a control group that slept the first night after learning, and b) The associated MR signal from the amygdala in both groups of subjects, demonstrating a significant reduction in limbic reactivity in those that slept the first night after learning, together with the magnitude of response from the same region to neutral stimulus recollection. Modified from Sterpenich V, Albouy G, Boly M, et al: Sleep-related hippocampo-cortical interplay during emotional memory recollection. PLoS Biol 5:e282, 2007⁶⁴; with permission.

Conclusion

When viewed as a whole, findings at the cellular, systems, cognitive and clinical level all point to a crucial role for sleep in the affective modulation of human brain function. Based on the remarkable neurobiology of sleep, and REM sleep in particular, a unique capacity for the overnight modulation of affective networks and previously encountered emotional experiences may be possible, redressing and maintaining the appropriate connectivity and hence next-day reactivity throughout limbic and associated autonomic systems. However, if the canonical architecture and amount of sleep is disrupted, as commonly occurs in mood disorders, particularly major depression and PTSD, this symbiotic alliance of sleep-dependent emotional brain processing may fail. The predicted consequences of this failure appear to support the development and/or maintenance of a number of clinical symptoms expressed in mood disorders, while the changes in sleep associated with common pharmacological treatments of these cohorts support a relief of these aberrant overnight processes, all of which lead to experimentally testable hypotheses which can serve to guide future research. Ultimately, the timeless wisdom of mothers alike may never have been more relevant: that is, when troubled “get to bed, you’ll feel better in the morning”.