© Springer Science+Business Media LLC 2018Eric Vermetten, Anne Germain and Thomas C. Neylan (eds.)Sleep and Combat-Related Post Traumatic Stress Disorderdoi.org/10.1007/978-1-4939-7148-0_23
23. Sleep, Declarative Memory, and PTSD: Current Status and Future Directions
ACSENT Laboratory and UCT Sleep Sciences, Department of Psychology, University of Cape Town, Cape Town, South Africa
Department of Psychological Medicine, Apollo Bramwell Hospital, Port Louis, Mauritius
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
KeywordsSleepDeclarative memoryPTSDImpaired memoryMemory processingMemory-related impairmentsMemory consolidation
Healthy sleep is critical for successful memory consolidation.
Both SWS and REM sleep play distinct but important roles in sleep-dependent memory consolidation.
PTSD-diagnosed individuals have poor neutral declarative memory in comparison with control individuals.
SWS and/or REM sleep disruptions may contribute to neutral declarative memory deficits in PTSD.
The empirical evidence for this hypothesis is examined as well as possible mechanisms underlying the hypothesis.
Healthy sleep plays a vital role in the encoding and consolidation of newly acquired memories. As noted elsewhere in this volume, individuals diagnosed with posttraumatic stress disorder (PTSD) do not, typically, experience healthy sleep, with disruptions at both REM and NREM stages. Furthermore, from a clinical neuropsychological perspective , the diagnosis of PTSD is also associated with marked memory impairment. Few empirical studies have, however, explored possible associations between disrupted sleep and impaired memory in PTSD . In this chapter, we will review (a) models of memory processing during sleep in healthy individuals and (b) characteristics of sleep- and declarative memory-related impairments in PTSD-diagnosed individuals. We will propose that disrupted sleep is a critical mechanism underlying memory impairments in PTSD.
Because much of the literature on the neuropsychology of combat-related PTSD is concerned with performance deficits on tests of neutral, non-affective declarative memory, we have chosen to focus here on the processing of such memories during sleep in veterans with the diagnosis. Other chapters in this volume focus on recent research into the consolidation of memories with affective or emotionally laden content, which is, of course, integral to our overall understanding of the neuropsychology of PTSD.
We begin our review by examining declarative memory processing during sleep in healthy individuals . This section focuses primarily on consolidation processes during sleep but also makes reference to the relationship between healthy sleep and optimal encoding. Next, we review, briefly, the characteristics of declarative memory impairment in combat veterans diagnosed with PTSD. Finally, we will propose that this particular profile of memory deficits might result from disrupted sleep interrupting encoding and consolidation processes.
Healthy Sleep Enhances Encoding and Consolidation of Declarative Memories
Memory traces can evolve from unstable initial representations (formed at the encoding stage, where a representation of an experience is registered in the brain) to fully fledged and stable images and narratives that may persist for years [46, 58]. The process of memory consolidation is responsible for this evolution; it ensures that the initial representation is resistant to decay (forgetting), and it may even be responsible for enhanced strength of the memory trace [54, 79]. In healthy individuals experiencing uninterrupted sleep, consolidation of declarative memories appears to occur throughout the night [22, 36]. In fact, it appears that the successive progression of sleep stages, from early-night slow-wave-rich sleep to late-night REM-rich sleep, promotes encoding as well as consolidation [20, 63, 80, 81].
Consolidation During SWS
Two different theoretical models have, from a neurophysiological basis, attempted to explain how declarative memory consolidation occurs during SWS. The active system consolidation theory (for reviews, see [12, 80]), incorporating findings from both the animal [61–64] and human [19, 43, 65] literatures, suggests that the same brain regions and functional connective systems active during encoding in wakefulness are reactivated during sleep. Specifically, this theory posits that memory traces encoded initially in both the hippocampus and neocortex are reactivated during subsequent episodes of SWS. During those stages of sleep , slow electrophysiological oscillations generated by the neocortex drive repeated reactivations of memory traces in the hippocampus. The upstate (represented as the peak of the wave formation on EEG recordings) of these slow oscillations synchronizes with sharp-wave ripple from hippocampal- and thalamic-driven spindles [34, 82]. This synchronization promotes the formation of ripple-spindle events, which in turn promote effective transfer of reactivated memory traces from the hippocampus to neocortical structures . Hence, the initially unstable and relatively weak memory traces based in the hippocampus are incorporated increasingly strongly into preexisting networks of knowledge stored in neocortical circuits; during later waking activation, these memory traces are therefore less reliant on hippocampal activation .
Various studies support these findings. Healthy participants asked to encode word pairs and then recall them later perform better when the delay is filled with the SWS-rich first half of the night than when it is filled with the REM-rich second half of the night or with normal waking activity [21, 47, 48]. Additionally, when waves specific to SWS (i.e., very slow cortical oscillations of <1 Hz) are induced in the prefrontal cortex (PFC) using direct current stimulation, participants in the stimulation condition have greater word-pair retention than no-stimulation controls [2, 44].
In contrast to the active system consolidation theory, the synaptic homeostasis theory [67, 68] suggests that the slow oscillations during SWS act to decrease, rather than increase, neural connections or synaptic strength. Specifically, this theory posits that whereas during waking, learning and memory processes act to increase synaptic strength, during sleep synaptic connections are downscaled so that circuits do not become saturated and therefore unable to encode information successfully the next day. A result of this downscaling is that while weakly potentiated synapses are eliminated, strongly potentiated synapses remain, thus ensuring better recall of relevant information .
Recent studies focusing on biological markers of synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) have provided some support for this theory. LTP is one key mechanism explaining long-lasting synaptic strengthening in neural networks; LTD, in contrast, is a process that selectively weakens specific synaptic connections over a period of hours, thus clearing them of old memory traces and allowing the potentiation of new traces . Glutamatergic AMPA receptors containing the subunit GluR1 have been found to play an important role in mediating LTP and LTD processes . Vyazovskiy et al. , studying the rat hippocampus and cortex, showed that, during wakefulness, the levels of this receptor were high; during sleep, however, they were low. Further, changes in the expression of this receptor were consistent with LTP during the day and with LTD during the night. Importantly, changes in slow-wave activity in the rat brain during sleep were associated with changes in synaptic efficacy, further supporting the hypothesis that SWS is associated with LTD and therefore with synaptic downscaling .
Are these two different models of the neurophysiological mechanisms underlying memory consolidation during SWS sleep compatible with one another? On the face of it, they are not: The active system consolidation model suggests a strengthening of synaptic connections, and therefore of memory traces , whereas the synaptic homeostasis theory suggests an overall decrease in synaptic connections. Nonetheless, several authors (e.g., [12, 80]) have suggested that these models are in fact complementary and together may explain discrete aspects of the consolidation process during SWS sleep. That is to say, the processes can operate simultaneously: While active system consolidation may strengthen memory traces and integrate them into wider and preexisting networks of information, synaptic downscaling may eliminate superfluous neural connections and refresh synaptic potential for encoding. Furthermore, and with specific regard to memory consolidation, one set of hypotheses  suggests that these processes work together to improve signal-to-noise ratio : When superfluous neural connections are eliminated, the connections that remain have greater overall strength, thus ensuring optimal consolidation. In a recent update on the state of the art, Genzel et al.  suggest that these two models of sleep-dependent consolidation can be further reconciled by understanding the distinction between light NREM sleep (NREM 1 and NREM 2) and deep NREM (SWS). These authors argue that slow oscillations, sharp-wave ripples generated in the hippocampus, and surface EEG indicators (such as K-complexes and spindles) represent global markers of active system consolidation which is strongly (but not exclusively) associated with light NREM sleep. They furthermore propose that slow-wave activity and delta waves are local markers of synaptic homeostasis, which dominates over replay mechanisms related to active system consolidation in SWS. Each successive cycle of lighter and deeper NREM sleep results in the reorganization of information and removal of superfluous connections, respectively, which leads to optimal memory consolidation. Further research is still needed to demonstrate exactly how these processes may work alongside each other.
Consolidation During REM
There is evidence for two distinct memory consolidation processes, each based on discrete electrophysiological events, during REM. The first process involves ponto-geniculo-occipital (PGO) waves. In rats, PGO density during REM increases following learning [10, 11, 69]. This increase is associated with post-sleep task performance improvements. Furthermore, PGO waves are associated with the expression of immediate early genes (IEGs) , which express during LTP in REM sleep and result in long-term synaptic strengthening in the brain . Following learning, IEG activity is localized to brain regions which were involved in the acquisition of new material [52, 53, 69]. A recent study also demonstrated that if REM sleep is selectively deprived after learning in rats, both memory consolidation and LTP are impaired .
The second electrophysiological process that promotes memory consolidation during REM is the expression of the theta rhythm [3, 12]. During waking, theta activity occurs during the encoding of hippocampal-dependent memories . During sleep, there is evidence of neuronal replay, associated with theta activity, of this encoded information in the hippocampus [40, 49]. Furthermore, in mice, silencing of REM-specific theta rhythms only (i.e., leaving intact those rhythms during other stages of sleep) selectively impairs consolidation of, for instance, neutral information related to novel object place recognition . In humans, theta activity during REM increases after the learning of word pairs before sleep . Current research shows that theta rhythm and PGO waves are related, in that PGO waves are phase-locked to theta rhythm . In animal models, eliciting theta waves during REM sleep in the medial septum entrains PGO waves to the theta rhythm. In humans, PGO waves are impossible to measure given the current technology because they occur in medial regions of the brain and are not easily detected via surface EEG . Hence, the relationship between theta rhythm and PGO waves, and their distinct or overlapping contribution to memory consolidation, remains unclear in humans.
In summary, these theoretical frameworks and empirical data help explain why the progression of sleep stages over the night results in optimal memory consolidation. During early-night SWS, relevant memory traces are selected (by the strength of their potentiation at synapses; weak connections are eliminated) and integrated into preexisting networks of knowledge. During REM sleep, these traces are strengthened so that they form long-lasting representations in the brain. Of note here is that IEG activity is correlated with EEG spindle activity during the preceding SWS. One hypothesis, then, is that SWS primes networks for later IEG expression .
Encoding Following Sleep
Numerous empirical studies have shown that acquisition of newly-presented declarative information is more efficient after a session of uninterrupted sleep than after a period of sleep deprivation or after a session of fragmented sleep. For instance, Harrison and Horne  showed that healthy participants who had been sleep deprived for 36 h performed significantly more poorly on a face recognition task than those who had slept for the normal 8 h prior to testing. Even when a subgroup of the sleep-deprived participants was administered caffeine to combat non-specific effects of lower alertness, the sleep-refreshed group performed better.
There is a clear neural basis for these between-group differences. Functional MRI studies exploring the sleep deprivation and memory testing paradigm described above have shown that, compared to those who sleep normally, sleep-deprived individuals have less medial temporal lobe (and, specifically, hippocampal) activation and greater (perhaps compensatory) PFC and parietal activation [13, 86]. Because, in these studies and in others (e.g., [14, 59, 87]), successful encoding is associated with extent of hippocampal activation, it appears that healthy sleep is important in preparing the appropriate neural circuits for next-day acquisition of novel information.
These empirical data are consistent with the theoretical frameworks outlined above. By the active consolidation model, one proposed result of the dialogue between the neocortex and hippocampus during SWS is that retrieval of “old” memories is less reliant on hippocampal involvement during subsequent (daytime) reactivations. Similarly, the synaptic homeostasis model posits that, upon waking, hippocampal networks are refreshed as a result of synaptic downscaling during SWS. Both theories, then, predict that the hippocampus will be refreshed and ready for new encoding after a night of healthy, uninterrupted sleep.
Declarative Memory and Sleep in Combat-Related PTSD
A key feature of the neurocognitive profile of PTSD is declarative memory impairment (for reviews, see, e.g., [6, 31, 60]). These impairments are (a) independent of performance on tests of attention (i.e., impaired memory is not a secondary effect of impaired attention ) and (b) not significantly associated with level of depression or with degree of past alcohol abuse [26, 30]. Furthermore, neuroimaging studies suggest that, in PTSD, decreased hippocampal volume is associated with degree of declarative memory impairment [4, 66, 78, 85] and that individuals with PTSD show altered patterns of hippocampal/parahippocampal and PFC activation during associative learning and memory tasks [25, 83].
There are critical nuances to the pattern of declarative memory impairment in PTSD, however. Veterans diagnosed with PTSD tend to show deficits in the encoding of novel information, as well as in the delayed free recall of that information [5, 7, 57, 74–76]. These deficits in recall are not deficits in retention of information , however; that is to say, individuals diagnosed with PTSD perform more poorly at the encoding stage of list learning, word association, or story memory tasks and continue to perform poorly at delayed free recall, but they do not lose more information over the delay interval than do control participants (i.e., there tend to be no significant between-group differences when one uses percentage retention (the amount recalled after a delay as a proportion of what was learned initially) as an outcome variable) ([56, 74, 76, 78] but see [4, 5]).
The implication here, then, is that PTSD-diagnosed individuals have relatively stable memory performance after they have learned information during waking: They do not forget any more than controls do. One runs into a conundrum here: Retention ability is reliant on hippocampal activation [14, 15, 70]; PTSD-diagnosed individuals have decreased hippocampal volume and compromised hippocampal functioning [4, 78]; yet they do not forget previously learned information more readily than controls do [74, 76].
One possible way to explain this conundrum involves considering the patterns of sleep disruption present in PTSD. As other chapters in this volume note, SWS percentage tends to be lower in PTSD patients than in healthy controls [1, 35]. As explained in the preceding sections of this chapter, normal SWS acts to strengthen memories encoded during the preceding waking hours. It does so by replaying the functional connectivity of neural circuits involved in (a) the encoding of information and (b) the transfer of that information from the hippocampus to neocortical sites. This active consolidation process , along with the synaptic downscaling detailed by the synaptic homeostasis theory, leaves the hippocampus refreshed for next-day encoding as previous-day memory traces no longer rely heavily on hippocampal activation. In PTSD, however, SWS disruption may leave hippocampal networks saturated during next-day learning and memory tasks; hence, one observes the characteristic PTSD-related pattern of declarative memory (and especially encoding) deficits on these tasks.
Currently, however, there is little data directly addressing the role of disrupted REM sleep in explaining impaired consolidation of declarative memories in combat-related PTSD. As noted above, empirical studies have shown that, in healthy individuals, REM is also important for the consolidation of neutral non-affective declarative memories [52, 69]. Additionally, PTSD-diagnosed individuals have a different quality of REM sleep to controls; for instance, they have increased REM density  and REM fragmentation [24, 45]. Although SWS is strongly associated with the restoration of memory networks through active system consolidation and synaptic homeostasis that leave hippocampal and other brain networks refreshed for next-day encoding, a recent study showed that REM sleep is also implicated in restorative processes. Grosmark et al.  showed that firing rates are unexpectedly decreased during REM sleep in contrast with NREM sleep in the rat hippocampus, suggesting a downscaling of neuronal activity in preparation for next-day encoding . These results indicate that restorative processes which leave the hippocampus refreshed for next-day encoding might not be isolated to SWS (i.e., that REM sleep might also play a role in restoration). From this point of view, REM sleep disruptions may also contribute to the specific neutral declarative memory impairments demonstrated in PTSD-diagnosed individuals, which are characterized by poor daytime immediate and delayed recall.
In summary, the hypothesis here is that (a) disrupted consolidation in PTSD-diagnosed individuals occurs during nighttime rather than daytime, and that (b) a consequence of this disruption is the saturation of hippocampal networks, so that (c) these individuals have significant difficulty learning (but not retaining after learning) novel information during waking hours.
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Only three recent studies, from three different laboratories, have directly investigated memory processing during sleep in PTSD . First, van Liempt et al.  showed that combat veterans with PTSD (n = 13) experienced more fragmented sleep during the first, SWS-rich, half of the night than did trauma controls (i.e., veterans who had experienced trauma but who did not meet diagnostic criteria for PTSD; n = 15) and healthy controls (i.e., individuals who had never experienced a DSM-IV A1 criterion traumatic event; n = 15). Furthermore, relative to healthy controls, veterans with PTSD showed significantly lower plasma levels of growth hormone (GH) during the night. This latter finding is important because:
A recent study in rats showed a mediating relationship between sleep, GH, and normal synaptic function of the hippocampus , hence suggesting that GH secretion during sleep is closely associated with optimal memory processing.
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