THE ROLE OF REM SLEEP IN EMOTIONAL MEMORY AND AFFECTIVE REACTIVITY

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1 Chapter THE ROLE OF REM SLEEP IN EMOTIONAL MEMORY AND AFFECTIVE REACTIVITY IN HUMANS Tony J. Cunningham, Enmanuelle Pardilla-Delgado, Sara E. Alger and Jessica D. Payne University of Notre Dame, Department of Psychology, Notre Dame, IN, US ABSTRACT Rapid eye movement (REM) sleep is characterized by high levels of brain activity such that functional imaging during this stage of sleep indicates activity levels closer to daytime wakefulness than deeper stages of non-rem (NREM) sleep. While investigation into the functionality of this activity is relatively novel, research indicates that the high cholinergic and theta activity during REM sleep may optimize the consolidation of emotional experiences into long term memory traces. Interestingly, while REM sleep seems to enhance memory consolidation some evidence suggests that it simultaneously strips away the physiological affectivity initially associated with the emotional experience. In this chapter we will review the role of REM sleep in the consolidation of emotional salient information in humans. We will also Corresponding author. Address: University of Notre Dame, Department of Psychology, Haggar Hall, Room 122B, Notre Dame, IN

2 2 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. discuss the various reports of REM sleep s effect on regulating emotional brain reactivity. This will include an examination of the Sleep to Forget, Sleep to Remember (SFSR) theory of emotional memory processing which suggests that affective reactivity is systematically reduced following multiple iterations of sleep that includes REM. Finally we will consider how REM sleep dysregulation may play a role in the inability to effectively process emotional information seen in many forms of psychopathology, such as depression and post-traumatic stress disorder (PTSD). 1. INTRODUCTION The discovery of rapid eye movement (REM) sleep six decades ago (Aserinsky and Kleitman, 1953) marks possibly the most significant breakthrough in sleep research to date. Overnight sleep was transformed from an impenetrable phenomenon shrouded in mystery into a distinguishable sequence of processes that could be broken into and studied by its component parts. While the last 25 years of research have led to a surge of potential mechanisms of sleep, including emotion regulation benefits (Yoo et al., 2007), brain waste removal (Xie et al., 2013), immune system function (Bryant et al., 2004), and insight and creativity (Stickgold and Walker, 2004), one of the most critical and well-researched benefits of sleep is memory consolidation. A wealth of evidence indicates that a period of sleep following learning preserves newly acquired knowledge better than an equivalent period of wakefulness (see Payne, 2011, Stickgold & Walker, 2013 for review). While many types of memory are aided by different stages of sleep, this chapter will focus exclusively on the impact that REM sleep has on emotional memory consolidation. Interestingly, along with creating durable memory traces of our emotional experiences, REM sleep has also been implicated in our ability to regulate our responses to these events as well. Accordingly, our discussion will focus on how REM sleep is involved both in the consolidation of emotional declarative memories and the processing of emotional reactivity tied to these events in humans. First, however, in order to understand why this particular stage of sleep is important in processing emotional information, it is necessary to introduce the unique physiology and neurochemistry of REM sleep that sets the stage for this type of processing to occur.

3 The Role of REM Sleep in Emotional Memory 3 2. PHYSIOLOGY AND NEUROCHEMISTRY OF REM SLEEP In a typical night of sleep, the brain and body progress through different stages, generally delineated as non-rapid eye movement sleep (NREM, Stages 1-4) and rapid eye movement sleep (REM), in approximately 90-minute cycles. In the early night, these cycles are rich in slow wave sleep (SWS, Stages 3 and 4), while REM sleep increases reciprocally as the night progresses, with REM-rich sleep occurring in the late night/early morning (see Figure 1). Neural activity is high and widespread during REM sleep, in some areas even more active than what is seen during waking experience, notably in the visual cortex, limbic lobe and hippocampus. REM sleep is characterized by tonic periods of low amplitude, desynchronized electroencephalographic (EEG) activity, often described as saw-tooth waves, and decreases in muscle tone accompanied by phasic saccadic rapid eye movements, muscle twitches, fluctuations in heart rate, body temperature, and respiration rates (Aserinsky & Kleitman, 1953; Rosenthal, 1998). Another notable component of REM sleep are the phasic PGO spikes, which are bursts of activity between the pons, lateral geniculate nucleus of the thalamus, and occipital lobe. These spikes may play a role in moderating the timing of the rapid eye movements (McCarley, 2007). (Payne, 2011). Figure 1. This profile represents the sleep architecture of a healthy night of sleep. Slow wave sleep dominates the first half of the night, but during the latter half, REM sleep is the majority.

4 4 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. Figure 2. Graphical representation of varying concentrations of neuromodulation across a variety of brain states. ACh = Acetylcholine, NE= Norepinephrine, 5-HT = Serotonin. The neurochemistry of REM sleep involves the interplay between REMoff and REM-on cells, primarily involving the neuromodulators norepinephrine, serotonin, and acetylcholine. The activity of the noradrenergic cells of the locus coeruleus and serotonergic cells in the dorsal raphe nuclei are significantly reduced or silenced, greatly reducing levels of norepinephrine and serotonin in the brain (Hobson et al., 1998; Rosenthal, 1998, McCarley, 2007). In response, cholinergic neurons in the pontine tegmentum, lateral pontine and medial medullary reticular areas innervating the hippocampus, thalamus, and hypothalamus are released from inhibition and activated during REM sleep (Maquet, 1997; Rosenthal, 1998; See Figure 2). Acetylcholine during REM sleep plays a role in inhibiting GABAergic, spindle-generating neurons in the reticular nucleus of the thalamus that are typically active during Stage 2 and SWS. This, in turn, releases other neurons in the reticular formation from suppression, allowing stimulation of cortical regions (Maquet, 1997; McCarley, 2007). Notably, levels of acetylcholine in the hippocampus are above what is seen during wake, resulting in the suppression of glutamatergic receptors and reduced connectivity and flow of information from the hippocampus to the neocortex (Hasselmo, 1999). The neurochemical environment created by these REM-on and REM-off neurons is conducive to integration of newly learned information into existing neocortical stores, semanticization of information, and promotion of flexible use of information throughout the cortex without hippocampal interference. Furthermore, regarding neural functional connectivity, there appears to be significant modulatory connectivity between the amygdala, the area of the

5 The Role of REM Sleep in Emotional Memory 5 brain primarily involved in emotional responses and emotional memory processing, and several key brain regions. While the subcortical regions discussed above widely enervate cortical regions, the amygdala modulates this activity, enhancing activity in some areas, such as the anterior cingulate cortex and the parietal operculum, above other cortical regions (Maquet, 1997). It is likely that this modulation during REM sleep, along with activation of the hippocampus, influences emotional memory storage in long-term cortical areas. Moreover, theta and gamma oscillations from the hippocampus during REM sleep are thought to facilitate this memory consolidation. Following consolidation processes beginning during SWS, during which hippocampal sharp wave ripples take place in reactivating the neural networks representing recent memory traces, theta and gamma oscillations play a role in the integration of these reactivated memory traces into long-term stores in the neocortex (Buzsaki et al., 1994). 3. REM SLEEP AND EMOTIONAL MEMORY CONSOLIDATION Emotionally salient information is biologically important and adaptive to remember. Experiences that evoke a feeling of negativity or positivity and are arousing are important to remember to inform future action, such as remembering that a snake bite will harm you. Even without sleep, emotional content has been shown in a consistent manner to be better remembered than neutral content in both healthy participants (e.g. Bradley et al. 1992; Cahill and McGaugh, 1998; see for review Kensinger, 2009; McGaugh, 2004) and amnesiacs (Hamann et al., 1999). However, a period of sleep, REM sleep in particular, seems to provide additional emotion-specific benefits to memory when compared to a similar time spent awake (e.g. Hu, et al., 2006, for review see Walker & van der Helm, 2009; Payne & Kensinger, 2010). For instance, Hu and colleagues (2006) showed participants a set of emotionally arousing and neutral pictures before a full night of sleep or before a wakefulness delay. At recognition, only participants that had slept indicated that emotional pictures were more familiar than neutral pictures. While this traditional sleep study design has often been utilized to demonstrate that sleep in general benefits the consolidation of emotional memory, only a smaller subset of studies have directly investigated the role of REM sleep in emotional memory processing.

6 6 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al Behavioral Evidence for a Role of REM Sleep in Emotional Memory Processing The close relationship between REM sleep and emotional memory processing had been suggested by early studies on dreaming in which dream reports after REM were full of more vivid and emotionally loaded details compared to the more thought-like dreams of other sleep stages (Foulkes, 1962; see Payne & Nadel, 2004). The first direct evidence in humans for a role of REM sleep in memory consolidation came from REM deprivation studies, some of which also had a focus on dreaming (Cartwright et al., 1975; Empson & Clarke, 1970; Greenberg, 1970; Greenberg, et al., 1983; Grieser, et al., 1972; Tiley & Empson, 1978). In one of the first studies assessing REM sleep s role in memory for emotionally-charged information participants were either REM-deprived, NREM-deprived, or spent a full day awake (Grieser et al, 1972). In this study participants were asked to complete anagrams at encoding, half of which were unsolvable (negative; a threat to self-esteem ) and half of which were solvable (neutral; non-threating ), and were later asked to recall as many words as possible from both sets. Both sleep groups recalled an equivalent number of non-threating words and also performed significantly better than those that remained awake. Interestingly, the NREMdeprived group recalled more threatening words than the REM-deprived group. The authors concluded that NREM sleep plays a positive role in the retention of neutral material while material with affective components is dealt with during Stage REM sleep (Grieser et al, 1972). In a similar study, participants who were REM-deprived were not able to retrieve emotionally meaningful memories when compared to NREM-deprived and normal sleep controls (Greenberg et al., 1983). Although these studies emerged with a hopeful start, REM sleep deprivation procedures were highly criticized because of the effects caused by the stressful and arousing repetitive awakenings throughout the night (Born & Gais, 2000; Horne & McGrath, 1984), with results speaking more to the damaging effects of deprivation rather than the natural consolidation processes happening during normal sleep. To overcome this limitation, Wagner and colleagues (2001) attempted to assess the role of REM sleep in emotional memory consolidation by taking advantage of the natural sleep rhythm (Wagner et al., 2001); namely, the first half of the night of a normal, healthy night of sleep is dominated by SWS while the second half of the night is dominated by REM sleep (see Section 2). In this study participants learned neutral and emotional texts in one of two conditions. In the first condition, the

7 The Role of REM Sleep in Emotional Memory 7 texts were encoded at 10:15pm, followed by three hours of early night sleep, and then subjects were awakened in the middle of the night (2:00AM) for a recall test 15 minutes later to account for sleep inertia. Conversely, the second condition had subjects sleeping the first part of the night, waking in the middle of the night (2:00AM) to learn the texts, followed by three hours of late night sleep (6:00AM) and recall at 6:15AM. Results showed that the REM-rich late sleep condition had higher retention for the emotional texts when compared to retention of neutral texts than the SWS-rich early sleep condition. The late sleep group also had significantly higher retention for emotional texts when compared to a control late wake group (i.e., late sleep deprivation). Critically, these findings cannot be solely explained by circadian differences because, even if cortisol is naturally higher in the second half of the night, there were no group differences between the late sleep and wake groups in cortisol levels. When these participants were called back after four years of the initial experiment a sleep-based benefit was still apparent but only for the emotional texts (Wagner et al., 2006). Wagner and colleagues used structured phone interviews to assess memory after 4 years via free recall, cued recall, and recognition tests. While free recall and cued recall turned out to be insensitive measures to reveal residual memory traces after the long time interval, forced-choice recognition tests resulted in highly significant differences for the sleep groups when compared to the wake groups. Nonetheless, this effect was not dependent in whether participants slept early or late, and authors explained that post-recall sleep in the early sleep group, which would have been REMrich, could have reconsolidated memories, abolishing any differences between early and late sleep conditions. Nishida and colleagues (2009) investigated how REM sleep physiology during a 90-minute nap affected consolidation of emotionally negative pictures vs. emotionally neutral pictures. Specifically, participants encoded a set of negative and neutral pictures and either slept or remained awake during a subsequent delay. Then all subjects encoded a second set of pictures, followed by a recognition test on all the material. The authors expected that the nap group would be able to remember more negative pictures than the no-nap group, but only from the first set, since the second set was encoded and consolidated in a similar brain state for both groups (i.e. the second set occurred after the nap group had already slept and would not have benefitted from off-line consolidation). Results showed that only the nap group demonstrated better recognition memory of emotional pictures encoded before the delay, compared to those encoded just before the recognition test. Such difference was not found in the no-nap group and recognition of neutral

8 8 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. material was similar across both groups and both time conditions. Correlational analyses showed that both the total amount of time spent in REM (min) and percent of total sleep time spent in REM (REM%) were positively related with the offline difference in emotional memory recognition (i.e. the change between memory from the first set to the second set of pictures). This shows that the sleep-dependent benefit of emotional memory recognition is directly dependent to the amount of REM sleep obtained in the 90-min nap: the more REM obtained, the larger the memory benefit. Additionally, they found a negative correlation between this difference score and REM sleep latency, showing that the faster participants entered REM, the larger the memory benefit. Finally, the authors assessed whether distinct electrophysiological oscillations (i.e. theta waves) were related to this offline difference. As mentioned earlier, the theta band is of noted importance because there is a clear relationship between emotional processing and theta oscillations in limbic (including hippocampus and amygdala) and prefrontal regions (Jones & Wilson, 2005; Pare et al., 2002). Results showed a positive correlation only between the offline difference score and right-lateralized prefrontal theta oscillations. In fact, no other correlations were found between the difference score and other frequency bands (i.e. beta, alpha, delta). In a study similar to Wagner et al. (2001), Groch and colleagues (2013) using the split night (early vs. late sleep) paradigm found that participants in the REM-rich late sleep condition remembered more emotionally negative pictures than in the SWS-rich early sleep condition. In agreement with this, a significant benefit for emotional over neutral pictures was seen in the late sleep condition that was not found in the early sleep condition. Similarly to other studies (Nishida et al., 2009; Payne et al., 2012) the authors found a positive relation between the relative amount of REM sleep in the late sleep condition and memory for the emotional pictures. Additionally, Groch and colleagues (2013) measured event-related potentials (ERP) during encoding and retrieval and were interested specifically in the frontal late positive potential ( ms after stimulus onset), a marker of recognition accuracy (Rugg et al., 1988). Recognition performance of old negative pictures ( hits ) referenced to new negative pictures ( correct rejections ) after late sleep was associated with significantly increased positivity ERP over frontal areas, while this was not the case in the early sleep condition. This increased late positive potential could reflect theta activity emerging in REM sleep coherently in the amygdala and other memory-relevant brain regions (Popa et al., 2010).

9 The Role of REM Sleep in Emotional Memory 9 (Payne, Chambers, & Kensinger, 2012). Figure 3. The emotional memory tradeoff effect refers to better memory of emotionally negative objects, compared to neutral objects (black bars), at the expense of lower memory for negative backgrounds, compared to neutral backgrounds (white bars). In addition to being beneficial for the formation of general emotional memories, sleep has also been found to be valuable for the selective consolidation of specific components of emotional memories. Payne and colleagues (2008) showed participants complex scenes composed of negative or neutral foreground objects on neutral backgrounds (e.g. snake in a jungle or squirrel in a forest, respectively) before a delay filled with a full night of sleep or daytime wakefulness. A surprise recognition test after the delay in which foreground objects and backgrounds were separated and presented individually (e.g. the squirrel or the forest, alone) showed that participants that slept had better recognition for the negative objects (e.g. snake) when compared to the wake group, but also poorer memory for the backgrounds initially paired with these negative objects (e.g. jungle) when compared to the wake group (see Figure 3). This emotional memory trade-off suggests that sleep does not necessarily benefit consolidation of all the information we encounter, but that specific (emotionally salient in this case) components are preferentially selected by sleep-dependent consolidation processes. In agreement with this idea and Nishida et al. (2009), the authors found in a follow-up study that memory for the emotional foreground objects (e.g. snake) was positively

10 10 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. correlated with time spent in REM and REM% (Payne et al., 2012). That is, the amount of REM obtained in a full night s sleep predicted memory only for the emotionally salient stimuli. Interestingly, when comparing memory over longer delays (12hr to 24hr), this trade-off is not only protected but magnified by sleep occurring soon after encoding, rather than the deterioration of the trade-off effect seen in a group of participants that waited ~16hr to sleep (wake 1 st group in Payne et al., 2012). This finding shows the that selectivity of sleep-based consolidation is maximized when the placement of sleep occurs right after learning, rather than after a delay, and that simple interference accounts cannot explain these results because all conditions obtain the same amount of waking interference (Wixted, 2004; Mednick et al., 2011). That is, memory is not better simply because of a lack of interference between encoding and retrieval. Some would argue that this emotional memory trade-off is only an encoding phenomenon dominated by attentional factors (Loftus et al., 1987; Reisberg and Heuer, 2004; Talmi et al., 2008; Niu et al., 2012), and the reason that the emotional components are better remembered later on is simply because they attract more attention. The comparison of a 12 hr delay to a 24hr delay by Payne et al. (2012) argues against this idea because if that were the case, both delay conditions should have similar memory for scene components. As mentioned, sleeping (first) right after encoding lead to an increased trade-off from 12 to 24hr, while being awake first abolished the tradeoff from 12 to 24hr, suggesting that active consolidation processes during sleep also play a role in this emotional-over-neutral preference for memory as well as protecting the memory from subsequent interference Neuroimaging Evidence for a Role of (REM) Sleep in Emotional Memory Processing Neural connectivity research indicates that the amygdala is important for emotional learning through its modulation of the memory centers (e.g. hippocampus) of the brain (Cahill et al., 1996; Dolcos et al., 2005; Labar & Phelps, 1998; for review see McGaugh, 2004). Hippocampus modulation by the amygdala, through direct and indirect pathways, has been observed during encoding, retrieval, and consolidation (see Petrovich et al., 2001 for review). Early studies showed an increase in activity in limbic regions (including the amygdala) and the hippocampus during REM sleep (Maquet et al., 1996; Nozfinger et al., 1997).

11 The Role of REM Sleep in Emotional Memory 11 In a more recent study, participants encoded negative and neutral pictures and either were then either sleep-deprived or slept normally (Sterpenich et al., 2009). They returned 3 days and 6 months later for recognition testing. At the 3-day retrieval test, those who slept not only had better memory but also had higher activation in the hippocampus and the medial PFC compared to those that were sleep deprived. Also, functional connectivity between these two regions was enhanced during recognition of emotional compared to neutral items, in agreement with their previous findings (Sterpenich et al. 2007). At 6 months, responses associated with recollection of emotional items in the sleep group were associated with activity of the ventral medial PFC and the precuneus (important for retrieval: Henson et al., 2005; Cavanna and Trimble, 2006), and the extended amygdala and the occipital cortex, but no longer the hippocampus. This supports the idea that systems consolidation of declarative memories involves a reorganization of memory traces, transferring neural representations from the hippocampus to the neocortex (Takashima et al., 2006; Diekelmann & Born, 2010). Additionally, the functional connectivity between the extended amygdala, vmpfc, and occipital cortex was enhanced in the sleep group relative to the sleep-deprived group. These results show that sleep is paramount in the involvement of the amygdala modulating the emotional memory network. Payne and Kensinger (2011) investigated the effect of sleep vs. wake on the emotional memory tradeoff effect in a functional MRI (fmri) experiment where scanning occurred during recognition testing. Successful retrieval of emotionally negative objects activated a widespread network of brain regions (including lateral prefrontal, parietal, and medial-temporal regions) for those participants who were awake between encoding and retrieval. For those who slept, a more refined network was recruited that included the amygdala, vmpfc, and cingulate gyrus (similar to Sterpenich et al., 2009 at 6 months). Additionally, for the sleep group when compared to the wake group, stronger connectivity was found between hippocampus, vmpfc, and amygdala during retrieval of emotional objects. Previous fmri studies have identified activity and connectivity of the hippocampus and the amygdala as necessary components of emotional memory retrieval, and thus these findings support the idea that sleep strengthens and refines this network for optimal emotional memory processing (Dolcos et al., 2003, 2005; Kilpatrick & Cahill, 2003; Ritchey et al., 2008).

12 12 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. 4. REM SLEEP AND AFFECTIVE REACTIVITY Often when faced with a distressing situation or a difficult decision, friends and loved ones will advise us to sleep on it, things will seem better in the morning, and certainly most of us can anecdotally recall a time in which a night of sleep has improved our disposition or made the answer to an emotional decision more apparent. But what is it about this respite from conscious processing that allows us to weather our internal emotional storm and come out the other side with a clearer perspective? New evidence seems to indicate that sleep, specifically REM sleep, may not only have an active role in enhancing memory for emotional information, but it may also play a part in how we react to emotionally salient situations as well. Emotionally salient stimuli consistently elicit increased subjective ratings of arousal and greater physiological responses compared to their neutral counterparts (Lang et al, 1993; Lang, 1995). The degree of response induced by an emotional stimulus depends on the intensity of arousal that the viewer associates with it (Lang et al., 1993) with greater arousal triggering greater physiological changes in heart rate (HR), skin conductance response (SCR), facial movements (electromyogram; EMG; Lang et al., 1993; Pace-Schott et al., 2011), event-related potentials (ERPs; Diedrich, et al., 1997; Schupp et al., 2006), and amygdala activation (Garavan et al., 2001). Recently, a debate has arisen in the literature as to whether a night of sleep, and REM sleep in particular, potentiates (increases), stabilizes, or depotentiates (decreases) autonomic reactivity to these negative stimuli Evidence for a Potentiating Effect of Sleep on Reactivity In one early attempt to address this question, a study was done to assess subjective affective responses to emotional stimuli after either early SWS-rich or late REM-rich periods of nocturnal sleep (Wagner et al., 2002). Those that were allowed three hours of REM-rich sleep reported a significant increase in aversiveness to negative scenes, while those receiving 3 hours of early SWSrich sleep claimed not to have any change in reactivity from baseline ratings. A follow up study was done allowing participants to receive a total night of sleep and again they found a shift in subjective ratings indicating increased reactivity, comparable to that seen after the late night REM-rich sleep (Wagner et al., 2002). Wagner and colleagues (2002) theorized that the increase in reactivity after REM sleep suggests a proactive priming-like influence of

13 The Role of REM Sleep in Emotional Memory 13 sleep in which familiar stimuli are processed differently than unfamiliar stimuli leading to an amplified emotional response at the second viewing. In a separate study by Lara-Carrasco and colleagues (2009) the amount of REM sleep was manipulated by allowing subjects to receive either an undisturbed night of sleep or a night of sleep in which the experimenter limited REM sleep through partial REM deprivation (REMD). Participants were asked to rate negative scenes both before and after sleep delays and they found that subjects in the REMD reported reduced reactivity compared to those that received a normal night of sleep. From this the authors concluded that REM increases aversive reactivity to negative pictures (Lara-Carrasco, 2009). They also suggest that common markers of depression, such as increases in REM density and the first REM epoch, could play a role in decreased emotional adjustment ability and increased dysphoric mood, particularly in light of other studies that have indicated that REMD temporarily reduces these symptoms (Vogel et al., 1975; see section 4.5 for further discussion on Clinical Implications) Evidence for a Stabilizing Effect of Sleep on Reactivity A more recent study attempted to replicate the findings of Wagner and colleagues by again investigating how a period of nighttime sleep affects subjective reports of valence and arousal to negative pictures compared to a interval of daytime wakefulness (Baran et al., 2012). This time, however, the results indicated that subjective ratings of arousal were reduced for those that remained awake during the consolidation while those that slept reported equivalent ratings to that those seen at baseline encoding. Given that the sleep group s subjective reports were maintained across the delay while those that remained awake showed a reduction in reported reactivity, the authors concluded that sleep may actually protect and have a stabilizing effect of emotional salience. (Baran et al., 2012) One important caveat of each of the aforementioned studies is that they rely solely on subjective ratings of reactivity rather than objective visceral measures. Relying on self-report measures could possibly be more indicative of what the participants believe they should be feeling rather than what they are truly experiencing. Moreover, because the key results were typically based on baseline ratings done prior to sleep and sleep (especially REM sleep) bolsters memory for emotional information, memory of the initial rating at encoding may have affected the critical response after sleep (Groch et al., 2013). This confound was recently addressed by Groch et al. (2013) by

14 14 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. examining how subjective ratings and ERP responses to negative images was altered over a night of sleep. Based on previous research, the authors focused on the ms late positive potential (LPP) of the frontal cortex, a late time window previously linked to ERP positivity effects of arousal evoked by emotionally salient stimuli (Dolcos & Cabeza, 2002). They also manipulated the primary stage of sleep achieved by separating participants into an early, SWS-rich condition and a late, REM-rich condition. Subjective rating results replicated the findings of Baran et al. (2012), indicating no change from encoding to recognition in either sleep condition. Even more intriguing, no change was seen in ms LPP for either the SWS-rich or REM-rich conditions. These results further suggest that processing negative stimuli during sleep may not alter the emotional reactivity associated with such images (Groch et al., 2013) Evidence for a Depotentiating Effect of Sleep on Reactivity While the previous studies suggest that sleep may have a potentiating or stabilizing effect on emotional reactivity, an increasing number of studies using objective, physiological measures suggest that sleep (specifically REM sleep) may actually have a depotentiating effect on emotional reactivity. In one of the earliest investigations of this phenomenon, participants were shown some gruesome footage of an autopsy and then were either selectively REM deprived (REMD), experienced an equivalent number of NREM interruptions to a paired participant in the REMD group (NREM-I), or were allowed a normal night of sleep before a second viewing (Greenberg et al., 1972). The authors found that participants in the REMD condition demonstrated significantly less habituation than the participants in the NREMD and normal sleep conditions and concluded that REM sleep must be important for adaptation to a previously experienced anxiety-provoking situation. A more recent study utilized fmri to replicate these findings in a very similar design (Rosales-Lagarde et al., 2012). After completing an emotional reactivity task at baseline and repeating it 24-hours later, participants in a REMD condition showed an increase in behavioral emotional reactivity compared to the NREM-I group. During retesting, the NREM-I group also demonstrated activity decreases in numerous neural networks associated with emotional processing and a decrease in the ventrolateral prefrontal cortex indicating reduced need for top-down emotion regulation. After REMD, however, activation in these areas remained the same or increased, indicating that

15 The Role of REM Sleep in Emotional Memory 15 deprivation of REM sleep decreases our ability to behaviorally and neurally regulate our emotional responsiveness. Napping paradigms have also been used to investigate sleep s role in emotion regulation. One study investigated how a nap would affect reactivity during an emotional face recognition task (Gujar et al., 2011). Participants viewed affective faces (fearful, sad, angry and happy) at midday and then were separated into nap and no-nap conditions. Those that remained awake during the delay showed an increase in ratings of fear and anger expressions. Participants that napped showed a reduction in fearful expression rating, no amplification of anger or sad expressions, and a potentiation in ratings of happy facial expressions. Critically, sleep stage analysis indicated that only those that obtained REM sleep during the nap exhibited the greatest reduction toward fearful face stimuli and the largest enhancement of happy expressions. Another study examined how SCR, heart rate deceleration (HRD; a phasic response that maps onto the affective arousal of a stimulus), and facial EMG responses changed during a nap- or wake-filled delay after repeated intrasession viewing of negative scenes (Pace-Schott et al., 2011). They found that participants that were allowed to nap showed greater SCR and EMG habituation to previously viewed emotional stimuli compared to those that remained awake, but there was no difference in HRD measures between the groups. Interestingly, despite the decrease in visceral reactivity, the nap participants did not report a decrease in subjective ratings of arousal (Pace- Schott et al., 2011). The importance of sleep in modulating emotional affectivity has also been demonstrated in studies allowing a full night of undisturbed sleep. In a study by Cunningham et al. (Under Review), SCR and HRD measures were collected at encoding and recognition of negative and neutral stimuli. Between sessions, participants were dismissed for a 12 hour consolidation period of daytime wakefulness or nocturnal sleep. Those that slept showed a significant decrease in SCR and HRD activation from baseline to recognition, while the activation for those that stayed awake remained unchanged. Finally, a seminal fmri study examined how polysomnograph-recorded nocturnal sleep vs. daytime wakefulness would affect amygdala activation to emotionally arousing and neutral scenes (van der Helm et al., 2011). The authors hypothesized that the reprocessing of emotional stimuli that occurs during REM sleep s marked suppression of central adrenergic neurotransmitters (typically involved in stress and arousal responses) would decrease next-day brain reactivity to recently experienced emotional events. Results indicated that amygdala activity and subjective ratings of intensity to emotionally salient

16 16 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. scenes was reduced after a night of sleep while no change was seen for those that remained awake. In addition to the decreased amygdalar activity, the authors observed a potentiation in ventromedial prefrontal cortex (vmpfc) connectivity, again only after the sleep filled delay. The vmpfc has been shown to have top-down inhibitory effects on the amygdala making it an active component of successful emotion regulation in healthy, rested adults (Sotres-Bayon et al., 2004). Critically, sleep stage analysis revealed that reduced REM gamma EEG activity (a marker of decreased central adrenergic activity) significantly correlated with decreases in both amygdala and behavioral reactivity. With none of these changes seen in the sleep group, the authors concluded that the physiology of REM sleep is linked to overnight dissipation in brain activation and behavioral responses. (van der Helm et al., 2011) 4.4. The Sleep to Forget, Sleep to Remember Hypothesis This recent influx of studies supporting the theory that sleep assists in the depotentiation of reactivity has led to the rise of the Sleep to Forget and Sleep to Remember (SFSR) model of emotional-memory processing (van der Helm & Walker, 2009; Walker, 2009; van der Helm and Walker, 2012), portrayed graphically in Figure 4. According to this theory, the reason that emotionally salient information leaves more durable traces on memory than neutral information is because of the flood of autonomic and neurochemical reactions that occur during encoding of the event, setting the stage for long-term memory formation (McGaugh, 2004). Over time, however, recall of these memories does not elicit the same magnitude of affective reactivation as originally elicited during the experience, or even during previous episodes of recollection. The SFSR hypothesis suggests that an emotional memory is comprised of a memory and a significant affective tone. After a single night of sleep, the affective tone is partially reduced, and subsequent nights of sleep continue to chip away at the blanket of emotional salience until only the memory remains (van der Helm and Walker, 2012). For example, if an individual loses a beloved family pet it is likely that they will be incredibly distraught for the first 24 hours. A week later they may still have periods of sadness, especially when a memory of their pet is triggered, but the emotional impact of this recollection is reduced from the initial experience of the loss.

17 The Role of REM Sleep in Emotional Memory 17 (Walker, 2009). Figure 4. A visual representation of the REM-sleep hypothesis of emotion regulation. When an emotional experience is first encoded it is wrapped in a very strong affective tone that initially helps consolidate the memory. After subsequent nights of sleep including REM, the emotional charge is stripped away until only the memory remains. Six months later pictures of the pet may still generate very vivid memories, but the negative emotional tone associated with the loss is greatly reduced and the sensation of loss could possibly even be replaced with positive feelings of the time spent together. van der Helm and Walker (2012) suggest that the unique neurobiological conditions of REM sleep offer the prime state for the decoupling of emotion from memory. During REM sleep, we sleep to forget the emotional tone, but sleep to remember the experience itself, and if this overnight therapy does not occur, the magnitude of emotional force could persist over time. Importantly REM sleep is comprised of three specific conditions, mentioned briefly earlier, that may make it so well suited for this important task. First, during REM sleep the limbic and paralimbic structures are highly activated, sometimes at levels even greater than wakefulness (Nofzinger et al., 1997; Nofzinger 2005), suggesting that we use this time to reactivate and reprocess previously encountered emotional experiences. Second, REM sleep s neurophysiology of theta oscillations in cortical and subcortical regions of the brain suggests network cooperation such that the details of an emotional event are strengthened through the development of new cortico-cortical connections resulting in enhanced memory representation but spread out across different

18 18 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. anatomical networks. Finally all of this processing occurs during the unique high-cholinergic neurochemistry of REM sleep in which aminergic concentrations (associated with stress and anxiety responses) are at their lowest (van der Helm and Walker, 2012). The SFSR model of emotional memory processing suggests that these distinct conditions of REM sleep work together to enhance the consolidation of emotional memory while simultaneously stripping away the affectivity originally associated with the event. Over time this process may allow us to be resilient to emotional or tragic events while still preserving the details of what occurred. 5. CLINICAL IMPLICATIONS Contemporary research on the role of REM sleep and emotional memory processing is focused on specific predictions of the SFSR hypothesis. First, the extent to which emotional traces are strengthened and affectivity is dissipated over time should be proportional to the amount of post-experience REM sleep, and perhaps how quickly one is able to enter into REM (REM latency). Critically, however, a pathological increase in REM sleep may strengthen negative memories to such an extent that concurrent efforts to reduce the affective tone may not be enough to combat the overwhelming influx of access to negative memories (Walker and van der Helm, 2009). Clearly the reduction of affectivity to an emotional event over time is adaptive. Evolutionarily there is no benefit in re-experiencing an embarrassing social situation or the loss of a loved one to an equivalent extent as we originally experienced it every time memory of the event is cued. Rather it is important for us to learn from the experience so that we can apply it to the next time a similar situation occurs. If successful separating of the emotion from the memory is not achieved in the first night of sleep following the experience, the SFSR predicts that the emotional tag tied to the memory will remain and we will continue to attempt to process the event on subsequent nights until successful decoupling is achieved (van der Helm and Walker, 2012). This may begin to explain the common types of sleep disturbance seen in a variety of affective disorders. Depression, for instance, is typically associated with an increase in REM (Tsuno et al., 2005). This pathological change may disproportionately amplify the strength of negative memories leading to the common occurrence of a negativity bias of memory for those with the diagnosis (Pyszczynski et al., 1989; Watkins, 2002). This over-consolidation of negatively arousing information and inability to strip away affectivity could

19 The Role of REM Sleep in Emotional Memory 19 create a perceived autobiographical history dominated by negative memory and may be why many attempt to process these events unsuccessfully with waking rumination. Additionally, the dramatic reduction of REM that follows the administration of many antidepressants would predict a reduction of this excessive consolidation of negative memory, but may also limit the ability to reduce the affectivity associated with the memories. (Walker, 2009) REM sleep disturbance and dreaming (nightmares) as well as increased sympathetic autonomic tone are also common features of Post-traumatic Stress Disorder (PTSD; Mellman et al., 1997; Lavie, 2001). The hyperarousal to trauma cues experienced by these victims indicate that they also may be unable to successfully decouple the affectivity of the event from the memory itself, causing them to virtually re-live the experience every time they remember it. While quantitative features of REM sleep may be important (e.g. time spent in REM, REM latency, etc.) attention is shifting to the qualitative features of this stage of sleep as well. Walker and colleagues (2012) suggest that the structure and physiology of REM sleep may play a particularly vital role in the persistence of PTSD symptoms. Most notably there seems to be a persistence of adrenergic activity during REM allowing for the emotional memory trace to be consolidated but blocking the brain s ability to depotentiate the associated reactivity resulting in amygdalar and behavioral hyperarousal. Support for this theory is mounting as pharmacological interventions that reduce adrenergic activity during REM sleep have shown recent success in reducing symptomology in PTSD patients. (van der Helm and Walker, 2012; Walker, 2009) 6. FUTURE DIRECTIONS As research techniques continue to grow more sophisticated, we are continuing to refine our understanding of the importance of REM sleep. As the latter half of the chapter indicates our understanding of REM sleep s role in emotional affectivity is still equivocal, but the picture is beginning to become clearer. This line of research clearly has exciting clinical implications, especially for mood and anxiety disorders. Further exploration into the function of REM sleep could be vital not only to our understanding of the underlying mechanisms of this disorder, but also in our ability to develop potential treatments. Interestingly, while the focus of this chapter was solely on the role that REM sleep plays in emotional memory processing, some recent evidence has

20 20 T. J. Cunningham, E. Pardilla-Delgado, S. E. Alger et al. begun to cast doubt on the idea that REM sleep is the only sleep stage involved in emotional memory consolidation. A few recent studies have indicated that there may be a role for NREM sleep in these processes as well (e.g., Groch et al., 2011; Kaestner et al. 2013), although this relationship is much less clear. Such findings may indicate that both NREM and REM sleep play a part in successful emotional memory processing and no single stage can make up for the entire milieu of conditions that occur during a full night of sleep. As noted at the beginning of the chapter, while the division of sleep was an important first step in research allowing us to break it down and get a better understanding of its component parts, sleep itself may be more than the sum of its parts. Future research should not only continue to refine our understanding of the stages of sleep but also should begin to integrate across findings to create a better understanding of sleep as a whole. CONCLUSION Mounting evidence suggests that REM sleep contributes to the active processing of emotional memory. It does so through a unique cascade of neurochemical and electrophysiological mechanisms that vary drastically from any other conditions that the brain experiences, creating the ideal opportunity for consolidating emotionally salient information. Naturally occurring REM sleep during both nocturnal and daytime sleep episodes have been shown to benefit emotional memory processing. Beyond simply preserving memories, the neural processes that occur during REM sleep may also play an important role in moderating our affective responses to previously encountered emotional stimuli, an idea that has exciting clinical implications. While much light has been shed on the crucial cognitive and emotional functions of REM sleep, developing a better understanding of the purpose of REM sleep and how it fits into the bigger picture of a full night of sleep remains a fruitful area for future research. REFERENCES Aserinsky, E., & Kleitman, N. (1953). Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science, 118(3062),

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