Beyond the neuropsychology of dreaming: Insights into the neural basis of dreaming with new techniques of sleep recording and analysis

Accepted Manuscript Beyond the neuropsychology of dreaming: insights into the neural basis of dreaming with new techniques of sleep recording and analysis Carlo Cipolli, Michele Ferrara, Luigi De Gennaro, Giuseppe Plazzi PII:

S1087-0792(16)30067-3

DOI:

10.1016/j.smrv.2016.07.005

Reference:

YSMRV 983

To appear in:

Sleep Medicine Reviews

Received Date: 16 November 2015 Revised Date:

14 July 2016

Accepted Date: 14 July 2016

Please cite this article as: Cipolli C, Ferrara M, De Gennaro L, Plazzi G, Beyond the neuropsychology of dreaming: insights into the neural basis of dreaming with new techniques of sleep recording and analysis, Sleep Medicine Reviews (2016), doi: 10.1016/j.smrv.2016.07.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title: Beyond the neuropsychology of dreaming: insights into the neural basis of dreaming with new techniques of sleep recording and analysis.

Running Title: Beyond the neuropsychology of dreaming

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Authors : Carlo Cipolli1, Michele Ferrara2, Luigi De Gennaro3, Giuseppe Plazzi4,5*

Affiliations: 1

Department of Specialty, Diagnostic and Experimental Medicine, University of Bologna, Bologna,

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Italy. 2

Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila,

L’Aquila, Italy.

Department of Psychology, Sapienza University of Roma, Roma, Italy.

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DIBINEM – Department of Biomedical and Neuromotor Sciences, University of Bologna,

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Bologna, Italy.

IRCCS – Istituto delle Scienze Neurologiche, AUSL di Bologna, Italy.

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Address correspondence to: *Giuseppe Plazzi, Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Altura 3, Bologna, Italy.

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Tel: +39 051 4966924; Fax: : +39 051 4966098;

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E-mail address: [email protected]

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ACCEPTED MANUSCRIPT Summary

Recent advances in electrophysiological [e.g., surface high-density electroencephalographic (hdEEG) and intracranial recordings], video-polysomnography (video-PSG), transcranial stimulation

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and neuroimaging techniques allow more in-depth and more accurate investigation of the neural correlates of dreaming in healthy individuals and in patients with brain-damage, neurodegenerative diseases, sleep disorders or parasomnias. Convergent evidence provided by studies using these

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techniques on healthy subjects has led to a reformulation of several unresolved issues of dream generation and recall [such as the inter- and intra-individual differences in dream recall and the

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predictivity of specific EEG rhythms, such as theta in rapid eye movement (REM) sleep, for dream recall] within more comprehensive models of human consciousness and its variations across sleep/wake states than the traditional models, which were largely based on the neurophysiology of REM sleep in animals. These studies are casting new light on the neural bases (in particular, the

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activity of dorsal medial prefrontal cortex regions and hippocampus and amygdala areas) of the inter- and intra-individual differences in dream recall, the temporal location of specific contents or properties (e.g., lucidity) of dream experience and the processing of memories accessed during

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sleep and incorporated into dream content. Hd-EEG techniques, used on their own or in combination with neuroimaging, appear able to provide further important insights into how the

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brain generates not only dreaming during sleep but also some dreamlike experiences in waking.

Keywords: Dreaming; dream recall; cognitive processes; REM sleep; EEG correlates; neuroimaging techniques; intracranial EEG recordings; state-/trait-like differences; videopolysomnography.

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ACCEPTED MANUSCRIPT List of Abbreviations: dl /l/ m/ vmPFC – dorsolateral / lateral/ medial/ ventromedial prefrontal cortex DTI – diffusion tensor imaging EEG – electroencephalography

Hd-EEG – high density EEG HDR/LDR – high/low dream recaller Hz – Hertz (cycles per second); REM sleep – rapid eye movement sleep NREM sleep – non rapid eye movement sleep

NIRS – near-infrared spectroscopy P300 – P3 wave (event-related potential) PET – positron emission tomography video-PSG – video-polysomnography

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PTSD – post-traumatic stress disorder

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MEG – magnetoencephalography

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(f)MRI – (functional) magnetic resonance imaging

PuM – medial pulvinar nucleus

RBD – REM sleep behavior disorder SEEG – stereo-EEG

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SOREM – sleep onset REM sleep SWS – slow wave sleep

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tACS – transcranial alternating current stimulation tDCS – transcranial direct current stimulation TMS – transcranial magnetic stimulation TMR – targeted memory reactivation TP(O)J – temporoparietal (occipital) junction V1/ V4/ V5 – visual area one/four/five

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ACCEPTED MANUSCRIPT 1. INTRODUCTION

Dreaming (also termed “sleep mentation”, “dream experience” or “mental activity during sleep”) is a state of consciousness occurring in a physiological condition different from that in which it

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becomes available for investigation via its recall (and possibly report). Because of the asynchrony between its generation during sleep and recall after awakening, dreaming has traditionally been considered difficult to study through the conceptual apparatus applied to investigate the states of

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consciousness experienced in wakefulness (for review1,2). This (often implicit) assumption has deeply influenced the experimental investigation of dreaming, first developed in the 1950s after the

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discovery of the cyclic architecture of sleep and the identification of rapid eye movement (REM) sleep as a possible neurophysiological marker of dreaming. However, recent neuroimaging and neurophysiological studies on resting state and mind wandering in wakefulness have shown a wide overlap of phenomenological features and underlying brain mechanisms3,4 with dreaming. This has

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led to a conceptualization of dreaming as a “natural” extension of waking consciousness5, namely, a state characterized by internally generated multisensorial (overall visual and auditory), motor (sometimes dramatic), cognitive and emotional experiences, inserted as fairly coherent events into

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an imaginary story-like plot3,6-8.

In this review, we will examine the deepening of our knowledge of the neurobiological basis of

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dreaming made possible by recent advances in electrophysiological and neuroimaging methods of sleep recording and analysis. To facilitate the understanding of the theoretical relevance of the findings obtained through these methods, we will start from an updated characterization of dreaming, as results from over 60 years of laboratory and clinical research.

2. FREQUENCY OF DREAM RECALL AND DREAM GENERATION PROCESSES The collection of dream reports after provoked awakening in the laboratory has provided both reliable estimates of the frequency of dream experience developed in the different sleep stages and 4

ACCEPTED MANUSCRIPT useful insights into the underlying cognitive processes, while the clinical observation of sleep and dream recall of patients with acute brain lesions has offered important evidence of the anatomical correlates of dream alteration and dream loss.

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2.1 Frequency of dream recall

Early laboratory studies using electropolygraphic recordings of sleep9-11 reported a much more frequent association of fairly long, perceptually vivid and complex (“dreamlike”) mental

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experiences after awakening from periods of sleep with heightened and desynchronized cortical activity (i.e., high-frequency/low-amplitude electroencephalographic [EEG] activity) accompanied

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by REMs, muscle atonia and increased variability in heart rate and respiratory activity, compared to other non-REM (NREM) periods of sleep (for review, see7,8).

The originally postulated close (if not exclusive) association of REM sleep and dreaming, however, was rapidly disproved by studies carried out using more complex designs and interview techniques

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(for review, see8,12), which yielded several crucial findings.

1) Dream recall is also fairly frequent (about 50%) after awakening from nighttime13-15 and daytime (in particular, stage-2) NREM sleep13,16 relative to REM sleep (more than 80%).

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2) One or more dreamlike characteristics (such as perceptual vividness, bizarreness, emotional tone and story-like organization) are enhanced in reports collected after late night NREM sleep (relative

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to the early night)15,17,18 and in the morning19,20, as well as after periods of total or partial sleep deprivation21,22 , restriction23 or with multiple awakenings24. 3) Neither dreaming nor REM and NREM sleep are stable, homogeneous and distinct states irrespective of terminology (for dreaming) and taxonomy (for sleep stages). Indeed, not only perceptual, but also cognitive contents (such as planning, reasoning and thinking) are common, as are emotional experiences (often intense and negatively toned25,26), in dream reports. Moreover, whole reports can rarely be classified as “dreams” or “thoughts”, but are better described along a continuum ranging from “thought-like” (overall in NREM sleep of early night15,18) to “dreamlike” 5

ACCEPTED MANUSCRIPT content (overall in REM sleep of late night17,18,27 and under higher sleep pressure21). Finally, 5 to 10% of NREM reports after stage 228 and stages 3 and 429 cannot be distinguished from REM reports solely on the basis of the perceptual and emotional features of their contents. 4) The stage- and cycle-related variations in recall frequency and in the perceptual, emotional,

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motor and story-like features of dream reports are influenced by large differences not only between (trait-like), but also within subjects (state-like). For example, there are opposite trends in the length and complexity of reports according to whether the time-in-stage pertains to REM or NREM sleep15

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and whether it is in the first or second half of the night18,30.

5) The frequency and characteristics of dream reports (and, thus, their within-subject variability) are

concern

the

modalities

of

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influenced, in particular, by situational and individual factors (for reviews31,32). Situational factors awakening

(abrupt/gradual33)

and

dream

reporting

(free

recall31/questionnaire32/affirmative probes34, guided recall35), and the presence/absence of interfering tasks upon awakening36. Individual factors concern gender, age, personality traits

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(openness to experience, psychological boundaries and absorption37), the tendency to suppress negative thoughts and emotions38 and the attitude toward dreams, motivation, emotional reactivity, and cognitive styles39.

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6) Individuals with normal or high recall frequency (once or more per week32,40) usually fail to report any dream after 5–30% of REM awakenings8, and some (so-called non-recallers) cannot even

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report any dream after REM awakenings31,41. 7) Dream recall can be modulated by dopamine agonists42,43, or even suppressed by brain lesions (see below) located at the temporoparieto-occipital (TPO) junction and ventromedial prefrontal cortex (vmPFC)44,45, without any appreciable effect on REM sleep frequency and duration or REM density46. The evidence that a more or less dreamlike mental activity is also developed during NREM sleep prompted researchers to reconcile the observed differences not only by postulating a continuum (ranging from purely thought-like to dreamlike features) of mental activities developed during all 6

ACCEPTED MANUSCRIPT sleep stages7,8,23,24., but also by attempting to overcome the boundaries of the traditional “neuropsychology of dreaming”, which was largely based on the neurophysiology of REM sleep in animal models. Recent advances in electrophysiological and neuroimaging techniques allow more in-depth (by monitoring the functioning of specific brain regions) and accurate (for segments of

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sleep close to awakening or marked by motor behaviors) investigation of the neural correlates of dreaming in healthy individuals and in patients with brain damage, neurodegenerative diseases, sleep disorders or parasomnias (see below). The indications so gathered may both complement

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those provided by the traditional electropolygraphic and clinical approaches and point towards the need to reformulate and test several unresolved issues of dream generation and recall within more

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comprehensive models of human consciousness and its variations across sleep/wake states.

2.2 Cognitive processes involved in dream generation and recall

Laboratory studies have consistently shown that dream contents result from the elaboration of

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several memory sources and not from a simple reactivation of previous events. An individual’s current concerns and everyday life events (so-called episodic memories) are seldom reproduced mechanically as dream contents47,48 but, rather, are largely transformed in combination with

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fragments of recent and remote events and items of semantic information49,50. Moreover, items of recent episodic information can be activated and processed not only over the following night (day

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residue effect51), but also up to 5-7 nights later (dream-lag effect51). Indeed, subsequent dreams reported after multiple awakenings of the same night show both repeated incorporations of presleep stimuli52-56 or suggestions and high frequencies of semantically equivalent or similar (socalled “interrelated”57,58) contents, regardless of the number of awakenings59, sleep stage60 or delay between awakenings. Both types of findings indicate that the activation of memories is not random, but oriented by some concerns61,62 and/or relationships with previously accessed information63. The fairly consistent findings on the dream-lag effect64-66 indicate that the cognitive processes subserving the functions of memory consolidation and emotional adaptation attributed to dreaming 7

ACCEPTED MANUSCRIPT are at work during both NREM and REM sleep (albeit with some differences65), also over a long period, with a selective advantage during REM sleep for personally relevant information66. Further investigating the dream-lag effect also seems important for the understanding of sleep-dependent memory consolidation and emotional balance (i.e., the different fate of emotional memories in

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normal subjects67,68 and in patients with post-traumatic stress disorder: PTSD69). Indeed, some neuroimaging and neurophysiological studies on the activation, during sleep, of the systems involved in (re)processing items of information that are emotionally and motivationally relevant

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(“salient”) to the individuals have suggested that their different functional outcomes may be accounted for in terms of consolidation (in patients with PTSD70,71) or depotentiation (in normal

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subjects72) of the negative emotional valence of events (for review71). In particular, the triage model73, which posits that salient information is ‘tagged’ for consolidation by emotional arousal, future relevance, and/or deliberate intention, stems from the evidence that the negative emotional tone of items of autobiographical memory fades faster over time than positive one74. Accordingly,

emotional charge72,75.

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sleep should provide a sort of overnight therapy for conflictual waking events and their negative

A full understanding of the relationships between dream generation and brain activity during sleep

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requires considering not only the fact that dreaming occurs in all stages and cycles, but also that its contents, which result from the processing (elaborative encoding76,77) of several memory sources,

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already reach some consolidation during sleep (obviously lower than in waking). Indeed, dreams can be retrieved at delayed recall (the next morning) without substantial changes in the amount and sequential order of contents35,78, compared with immediate recall (just after night awakening) and with short films watched some hours before79. Moreover, dreams may also persist in memory when retrieval fails, as shown by their successful recall when triggered by occasional real-life cues or prompted by appropriate probes (such as a short title given at immediate recall35) in a laboratory setting. Finally, when dream contents incorporate some parts of newly learned tasks (including their verbal, emotional, motor, perceptual and spatial components80-82), they may be also be accompanied 8

ACCEPTED MANUSCRIPT by higher consolidation of the tasks themselves at post-awakening retrieval. The latter finding suggests that, although the incorporation of pre-sleep tasks and suggestions is not a necessary step of their consolidation process (for review83), the elaborative encoding involved in dream generation may provide a further consolidation gain. This hypothesis raises the entwined issues of a) the

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possible cumulative consolidation effect of the repeated elaboration of recent information incorporated into dream contents82,84; and b) the (at least partial) overlap of the brain mechanisms responsible for the consolidation of recently acquired information and the elaborative encoding of

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dream contents during sleep. Both possibilities are intriguing given that, despite the wide “familiarity” (which also pertains to declarative memory) of characters and setting of dreams,

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episodic information is rarely (2%) replicated as a whole in dreams47,48.

The items of evidence in favor of the hypothesis that recent individually salient or task-related experiences are not only “reactivated”, but also further consolidated in the sleeping brain via incorporation into dream content, are still scant and discordant (for a discussion85). For example,

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visuomotor skills were shown to improve more after nighttime sleep in low dream recallers (LDR) compared with high dream recallers (HDR), although the latter had a higher rate of incorporation of the new (Mirror Tracing) task into dream content and a better initial performance86. At the present

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state of our knowledge, it, thus, seems more cautious to argue that: a) dreaming is not simply a function of the consolidation process of recent information, either replayed81 or associated with

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older memories during dreaming77; and b) only a part of the neural activity underlying dreaming, which is distributed across several cortical and subcortical structures, is influenced by the brain structures subserving different memory systems85.

2.3 Clinical studies of dreaming The early indications on the neural basis of dreaming were provided in the nineteenth century by the observation of the anatomical correlates of dream alteration or even cessation in patients with naturally occurring brain lesions87. However, it was only after the discovery of REM sleep that 9

ACCEPTED MANUSCRIPT clinical reports addressed the consequences of brainstem lesions and focal cortical damage to the mechanisms assumed to be responsible for the perceptual, emotional and formal properties of dream content88-89. The subsequent investigation of dreaming was based on the general hypothesis that lesions to pontine brainstem areas (which control sleep/waking cyclic organization90) reduce or

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suppress both REM sleep and dreaming91. Solms45 attempted to test this hypothesis by examining all cases of patients with acute brainstem lesions that included information relating to dreaming. His review showed that a drastic reduction of REM sleep was accompanied by complete dream loss (so-

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called Charcot-Wilbrand syndrome) in only one92 of the 26 reported cases, and in none of the 4 patients with large pontine lesions he examined himself44. However, as consciousness is usually not

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preserved when pontine lesions are severe enough to have a significant effect on REM sleep93-94, it cannot be argued that dreaming persists regardless of REM sleep (as suggested by Solms45,95). The theoretical interest of also ascertaining how other chronic subcortical lesions steadily modify dreaming is apparent. For example, some patients with bilateral damage to the basal ganglia (which

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causes an auto-activation deficit, namely absence of any self-reported thought in waking) can report very simple dreams after REM sleep96. This suggests that simple dream imagery is generated by brainstem stimulation and sent to the sensory cortex, while “full dreams” require that these

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sensations be “interpreted” by the cortical areas subserving higher-order cognitive processes. Several reviews on the outcomes of acute cortical lesions44,45,88,95,97,98 have addressed the role of the

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cerebral cortex in dreaming. These studies, which primarily attempted to test the hypothesis of the laterality of dreaming, consistently indicated that unilateral or bilateral temporoparieto-occipital (TPO) injuries are often (but not always) associated with a complete dream loss. The most comprehensive review (on 361 patients44) disclosed that dream loss usually follows damage localized in either of the following brain systems: 1) A posterior system, mostly unilateral (right), in or near the TPO junction. Lesions to this system affect dreaming44 as well as waking visual imagery99, while lesions to more specific regions (like V4 or V5) selectively affect dream representation of color45 or movement100. However, lesions to 10

ACCEPTED MANUSCRIPT primary unimodal sensorimotor cortices do not affect dream imagery45. Since visual imagery in turn shares approximately two-thirds of activated brain areas with visual perception, and especially visual association cortices99,101, both these findings support the hypothesis that dream experience, mental imagery and late stages of visual perception share some neural mechanisms. This is

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consistent with the finding that total dream loss in REM sleep persisted after the normalization of sleep architecture102 in a patient with bilateral occipital artery infarction (including the right inferior lingual gyrus).

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2) An anterior system, mostly bilateral, underlying the ventromedial (vm)PFC and including the white matter tracts surrounding the anterior horns of the lateral ventricles. Lesions to areas of this

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system are less frequently associated with dream cessation, which follows overall bilateral lesions to the white matter tracts surrounding the anterior horns of the lateral ventricles, underlying vmPFC. Many of these nerve fibers originate or terminate in the limbic system45,95. The ventromedial white matter contains dopaminergic projections to the frontal lobe, which are severed by prefrontal

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leucotomy. As one would expect from these findings, most leucotomized patients also complain of global cessation of dreaming45. Moreover, damage to the secondary visual areas of the medial occipital lobe/lingual gyrus leads to cessation of visual dream imagery, but leaves dreaming

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otherwise intact. On the contrary, lesions to the medial (m)PFC, anterior cingulate cortex and basal forebrain appear to be associated with increased frequency and vividness of dreams and with their

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intrusion into waking life44. In addition, lesions in the dorsolateral (dl)PFC, which cause waking deficits of self-monitoring and decision-making, have no effect on dreaming45 and no major changes in dreaming are associated with brain lesions, irrespective of their severity, in areas outside these two systems. Prospective studies on brain-damaged patients would be undoubtedly useful to better understand the neural basis of dreaming, as about half of these patients recover the ability to recall dreams at 2-4 years’ follow-up103. Nevertheless, the relationships between sleep normalization (i.e., neuronal reorganization associated with functional recovery after brain damage104) and changes in dream 11

ACCEPTED MANUSCRIPT recall and/or perceptual properties of dream content (possibly related to a reduction of visuoperceptive disorders) remain unexplored to a large extent in REM sleep and completely in NREM sleep. To sum up, a more or less dreamlike mental experience is developed during all sleep stages,

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although time-of-night, modality of awakening and technique of recall influence the estimates of dreaming and its content characteristics. Dream contents result from the re-elaboration of several memory sources, the processing of which may also exert some influence on their level of

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consolidation. Clinical studies on brain-damaged patients have provided fairly accurate indications

3. NEUROIMAGING STUDIES

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on the structures of two main (anterior and posterior) brain systems subserving dream generation.

Since the late 1990s, the findings of neuroimaging studies during sleep and the discovery that a default network of brain regions active during waking restful states is in part reactivated in REM

dreaming.

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sleep but de-activated in NREM sleep have advanced our knowledge of the neural correlates of

The advent of brain imaging techniques (in particular, positron emission tomography: PET; single-

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photon emission computed tomography: SPECT; structural and functional magnetic resonance imaging: s/fMRI) promised to cast light more directly on the relationships between specific dream

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features (as disclosed by report analysis) and brain activity during sleep. Indeed, the first (and only) PET and EEG study controlling the presence/absence of dream recall showed an activation during REM sleep in the pontine tegmentum, left thalamus, both amygdaloid complexes, anterior cingulate cortex and right parietal operculum, and a (bilateral) deactivation in a vast area of the dlPFC, parietal cortex (supramarginal gyrus), posterior cingulate cortex and precuneus105,106. These findings were fully compatible with the clinical observation that lesions in these areas do not affect dreaming. Two contemporary studies (without dream reporting107,108) disclosed a strong activation of the high-order occipitotemporal visual cortex (consistent with the vividness of many dreams) and 12

ACCEPTED MANUSCRIPT a concomitant decreased activation of the primary visual cortex during REM sleep. This dissociation is suggestive of a high-order visual processing during sleep, without external visual input and with a decreased activity of V1. The majority of subsequent neuroimaging studies (for reviews109,110) have shown substantial

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differences in brain activity during REM compared with NREM sleep, in which activation diminishes from waking levels107,111. In particular, REM sleep is characterized by an increased activity in the pons and midbrain, thalamus, basal ganglia, hypothalamus, ventral striatum and

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visual association cortices, and midline limbic and paralimbic areas, as well as in orbitofrontal and paracingulate cortices and in part of the medial prefrontal cortex (mPFC)105,107, whereas the

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dorsolateral prefrontal cortex (dlPFC) remains deactivated after the transition from NREM to REM sleep105,107,108,112. These indications prompt a reformulation of how the variations in brain activity and dreaming are actually associated, which may lead to the development of a new and more accurate neurophysiological model, enabling the testing of its predictions in studies on the trait- and

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state-like individual differences of dream generation and recall113.

The indications on the neural correlates of dreaming have been strengthened by the comparison of neuroimaging data of brain functioning concomitant with mental activities during sleep and resting

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wakefulness (such as daydreaming and mind-wandering). Indeed, some dreamlike features (such as visual imagery and bizarreness) had long been observed not only during stage-2 NREM at sleep

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onset14, in the late night15,17 and early morning19, but also in relaxed wakefulness114. However, the theoretical relevance of the latter finding only became apparent after the observation that the dmPFC is more active during mind-wandering compared with goal-directed intentional thinking115. This evidence complemented the indications provided by early PET studies, showing that some structures (anterior default network areas, vmPFC and portions of dmPFC, hippocampal and parahippocampal areas) are partially reactivated during REM sleep, while others (posterior parietal default network areas, especially the lateral inferior parietal and posterior cingulate cortex) remain deactivated105-108,111. With specific regard to the default mode network (DMN), both increased116 13

ACCEPTED MANUSCRIPT and decreased117connectivity between its nodes has been observed118 and distinct functions in dream generation have been hypothesized for its two subsystems. These are centered on the hippocampal formation (the medial temporal lobe subsystem, also called the simulation subsystem) and the dorsal medial PFC (the dorsal medial PFC subsystem, also called the self referential subsystem),

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respectively. The hippocampal formation might support dreaming, as it is more active in REM than NREM110,119,120, while the dorsal medial PFC (which shows incomplete connectivity during REM sleep117) might be responsible for the lack of insight into the current mental state, namely, the

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delusional acceptance of dreaming compared with waking internally-cued cognition120.

In general terms, many indications provided by lesional and neuroimaging studies have been

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combined to sketch models of the neurobiological bases of dreaming7,110,121. These models converge to suggest which brain networks may be responsible for modulating the most distinctive characteristics of dreams and dreamlike mental activities109,110,122: (1) activation of the amygdala complex, anterior cingulate cortex and orbitofrontal cortex could be related to the emotional

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features of dreams; (2) increased activation of the occipitotemporal visual cortex could be associated with visual dream imagery; (3) relative hypoactivation of the dlPFC could be associated with alterations in logical reasoning, working memory, episodic memory and executive functions,

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which frequently occur in REM sleep dreams; (4) activation of mesiotemporal areas, and specifically the hippocampus, could account for the episodic (recent and remote) memories

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commonly recognizable in specific dream contents. Notably, the involvement of the first two networks is consistent with the results of brain-lesion studies, while the role of mesiotemporal areas is supported by recent electrophysiological123,124 and morpho-anatomical findings125,126. Conversely, the neural bases of mind-wandering seem to involve more than just default network activity127, and several perceptual and emotional features of daydreaming seem to differ from those of REM and NREM daytime naps128. These partially discrepant findings clearly do not invalidate the models but, rather, prompt the elaboration of more specific hypotheses, which may be tested by applying complementary bottom-up (from lesional and 14

ACCEPTED MANUSCRIPT neuroimaging data to cognitive features of mental experiences129) and top-down research strategies (from dream phenomenology to brain maps121), and by using refined psychometric indicators to establish how the functioning of specific cognitive processes involved in dreaming (for example, working memory130) varies during NREM and REM sleep relative to wakefulness. Establishing

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how the variations in the activity of given brain areas are associated with specific features of dream content would also cast light on such crucial issue as the trait- and state-like individual differences of dream generation and recall113.

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The significant implications of the evidence from neuroimaging studies are not limited to cortical regions but also extend to subcortical nuclei. In particular, evidence for the metabolic decline of

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brainstem and thalamus during NREM sleep7 (both involved in generating cortical slow waves106) and for the increased activation in limbic and paralimbic structures during REM sleep105 suggests that the hippocampus and amygdala play important and complementary roles in dream generation and recall. This hypothesis is supported by evidence that: a) retrieving cues of fear-conditioning

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stimuli delivered before sleep affects the emotional tonality of dreams in REM and NREM sleep131; b) in waking, gamma-band coherence between rhinal cortex and hippocampus increases when a stimulus is successfully encoded132, while gamma activity increases in the entorhinal cortex layers

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projecting to the hippocampus when the stimulus is retrieved133. Consistently, a study on epileptic patients with PSG and fMRI recordings has shown that an increased rhinal–hippocampal coherence

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during REM sleep is predictive of dream recall and, thus, indicative of some consolidation of dream content134.

Moreover, the activity of the amygdala, which is involved in the encoding and retrieval of emotional memories and in the physical expression of emotions during wakefulness135, is higher during REM sleep compared to wakefulness105. The hypothesis that the emotional load in dreams is also related to amygdala activation121 has received some support from two MRI studies evaluating the differences in the brain tissue of the hippocampus-amygdala complex. The volume of gray matter and its microstructural alterations were measured by means of microstructural analyses of 15

ACCEPTED MANUSCRIPT brain MRI and diffusion tensor imaging (DTI) analysis. The first study, on normal subjects, showed that inter-individual differences in the emotional tone and bizarreness of dream contents reported in the morning are closely related with the differences in the brain tissue of the hippocampusamygdala complex125. The second study, on Parkinson’s patients, showed significant relationships

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between the visual vividness of dream reports and the volume of amygdala, thickness of the medial prefrontal cortex and hypodopaminergic activity, pointing to a specific role for the mesolimbic dopaminergic system in qualitative (but not quantitative) aspects of dream recall126.

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In summary, neuroimaging studies have identified several networks of brain structures involved in specific aspects of dreaming, whose functions have been ascertained in wakefulness. These

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observations have prompted studies on the role played by both cortical and subcortical nuclei in dream generation and their stage-related variations.

4. ELECTROPHYSYOLOGICAL CORRELATES OF DREAM RECALL

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Recent advances in sleep recording (such as multi-electrodes in healthy subjects and intracranial electrodes in epileptic patients) and in brain stimulation during sleep have led to new strategies to identify the relationships between specific dream features and the activity of their putative

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underlying brain structures. 4.1 Cortical recordings

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The traditional approach to the neural basis of dreaming, based on the cortical electrophysiology of sleep, has also been revitalized by the advent of multi-electrode recording techniques and quantitative analysis of EEG signals, which provide a good temporal resolution and an acceptable level of spatial resolution. Studies using these techniques have identified both the spatiotemporal characteristics of sleep and its underlying neuronal networks111,136, and suggested a plausible functional role of the fast- (≥25 Hz) and slow-frequency (1-4 Hz) oscillations during sleep compared to waking. In particular, fast oscillations, which, in waking, are associated with attention to stimuli and active cognition, during REM sleep are associated with the temporal binding of 16

ACCEPTED MANUSCRIPT imagery137, memory and perceptual processes involved in dreaming138,139. Moreover, the decline in phase synchrony (coherence) of EEG rhythms between distinct brain regions during sleep reflects a functional disconnection, possibly responsible for the lack of executive control and bizarreness of dream content110.

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Consistent with the above indications, the analysis of EEG power during sleep onset REM (SOREM) periods disclosed that increased alpha activity (at 11-13 Hz) is associated with the absence of SOREM dreams and the appearance of NREM dreams140. This finding has been, in part,

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confirmed by a study where, after awakenings from stage 2 NREM and REM sleep, dream recall was associated with a reduction in alpha power (of lower magnitude in REM sleep), mainly in the

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temporoparietal area141. The involvement of alpha activity in dreaming (overall in the right temporal area, but only during stage 2 NREM) was also observed in a study where frontal theta oscillations (5-7 Hz) were found to be positively related to dream recall after REM sleep142. This relationship was also found in REM sleep of early afternoon naps, in which dream recall proved to be positively

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associated with higher frontal theta activity and theta oscillations at 6.06 Hz compared with a norecall condition143. Taken together, these findings provide some support for the "state-like hypothesis" (for review113), according to which the variations in dream recall frequency after

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awakening from the same sleep stage may primarily depend on the contingent physiological state preceding the awakening.

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The apparent parallelism between the above findings and the close association of theta and alpha oscillations with memory encoding and retrieval while awake suggests that similar neurophysiological mechanisms may be responsible for the encoding and recall of episodic memories, both in wakefulness and during sleep. Indeed, a more efficient encoding of words and faces correlates with a lower alpha activity (10-12 Hz) in the right temporoparietal cortical region144, whereas an increased alpha power correlates with decreased memory performance145. Moreover, scalp recordings have shown that successful encoding and retrieval of declarative information are associated with increased theta power146. Finally, studies with intracerebral 17

ACCEPTED MANUSCRIPT recordings in waking have also shown that an increase in frontal theta oscillations at encoding is predictive of successful recall147, and mediates the interaction between PFC and medial temporal lobe148. Seemingly discrepant findings have been obtained using a 40-h multiple nap protocol (with 10

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sleep-wake cycles of 75-150 min each) 149. However, the observed association of dream recall with lower delta and sigma EEG activity in frontal and centroparietal derivations during NREM sleep, and with higher alpha and beta activity in the occipital cortex during REM sleep, may depend on the

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repeated offset and re-onset of sleep, which altered the ultradian and circadian rhythms that interact in modulating dream experience64, and, hence, the EEG predictors of dream recall.

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These findings raise the question of whether the association between EEG oscillations during sleep and successful dream recall reflects stable characteristics of sleep EEG in some subjects rather than temporary relationships. Pertinent evidence for the existence of trait-like inter-individual differences has been obtained by comparing the brain reactivity of HDR and LDR subjects to

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auditory stimuli delivered during wakefulness and different sleep stages. Both intra-sleep wakefulness and brain reactivity, measured by attention-orienting brain response (P300) and late parietal response to first names (presented among pure tones while subjects were watching a silent

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movie or sleeping) ave been shown to be higher in HDR than in LDR subjects123,124. These findings were in keeping with the "arousal-retrieval" model of dream recall, which posits that dream

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encoding depends on intra-sleep periods of wakefulness150. Regional cerebral blood flow has also been found to be higher in HDR compared with LDR subjects in the temporoparietal (TP) junction during REM sleep, stage 3 NREM and wakefulness, and in the mPFC during REM sleep and wakefulness123. The latter finding supports the notion that the TP junction has a key role in the production of mental imagery and the memory encoding of dream content, as its increased activity may facilitate orienting attention toward external stimuli and prompt intra-sleep wakefulness. Finally, by using a passive auditory oddball paradigm, a decrease in parietal alpha power (8-12 Hz) has been demonstrated when names, compared with tones, are presented in waking, and an increase 18

ACCEPTED MANUSCRIPT in parietal alpha power when they are presented during REM sleep123. The different effects of complex sounds on alpha power during wakefulness (decrease) and REM sleep (increase) suggest that the increased alpha power during REM sleep corresponds to either a short and transient increase in arousal or a cortical inhibition associated with sleep protection.

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The existence of some stable differences in the brain reactivity of HDR and LDR subjects during both sleep and wakefulness suggests that the ability to recall dream content may be associated with a particular cerebral functional organization, regardless of the state of vigilance, subserving the

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4.2 Intracranial EEG recordings

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functioning of some memory mechanisms involved in dream generation and/or recall.

Convergent indications have been provided by studies on patients with pharmacoresistant epilepsy, using techniques of sleep recordings with higher spatial resolution [i.e., Hd-EEG and intracranial stereo-EEG (SEEG)] to assess the spatiotemporal dynamics of peculiar EEG features. In keeping

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with the “local sleep theory”, which posits that the quantitative EEG features of each sleep stage are regionally and temporally modulated151,152, the regional differences in EEG activity at cortical and subcortical level may be indicative of specific functions in dream generation and recall. The activity

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of the mediotemporal lobe, thought to be involved in dream encoding and recall, has been studied using intracranial SEEG134, under the assumption that the encoding of such episodic information as

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dream contents during sleep could share some electrophysiological mechanisms with the encoding of other episodic information in wakefulness. Since a phase synchronization of rhinal–hippocampal EEG activity in the gamma range and an increased EEG coherence in the theta range had proved to be predictive of successful memory formation132, the indices of rhinal–hippocampal and intrahippocampal EEG connectivity were compared in REM and NREM sleep of patients139 who were or were not successful in recalling dreams after awakening. EEG coherence was higher for all the frequency bands investigated (from 1 to 44 Hz) in patients with successful dream recall compared with those with no recall, with a significant difference for all the states (waking, NREM 19

ACCEPTED MANUSCRIPT and REM sleep). Moreover, the higher connectivity was more apparent in the low frequency theta range, consistent with data on memory formation in wakefulness132,139. All these findings support the hypothesis that the consolidation of dream content and the formation of episodic memories are associated with increased mediotemporal connectivity in both REM and NREM sleep.

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Other SEEG studies have provided useful suggestions on the neurophysiological mechanisms underlying dream recall. Deactivation of the thalamic medial pulvinar nucleus (PuM) during REM sleep (indicated by the abundant EEG delta activity153), which is at odds with the general

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thalamocortical cholinergic activation, suggests the presence of deactivated cortical areas (directly connected with PuM) among other activated areas (connected with other thalamic nuclei). This

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dissociation could explain the reduced spatiotemporal cortical connectivity of REM sleep compared to waking154 and, albeit indirectly, the high frequency of bizarre contents of REM dreams as a consequence of the inactivation of specific cortical areas (such as posterior cingulate, dorsolateral

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prefrontal and parietal cortices) connected with PuM153.

4.3 Brain stimulation techniques during sleep

Transcranial stimulation techniques are able to disclose causal links between targeted brain areas

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and specific cognitive or emotional responses. In particular, transcranial direct current stimulation (tDCS) can modulate cortical excitability over frontocortical areas during slow wave sleep (SWS)

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without awakening subjects, and enhances declarative memory consolidation155. When applied to dream investigation, tDCS has shown that cathodal-frontal and anodal-parietal stimulation increases reports of visual dream imagery during stage 2-NREM156, but not during SWS157, and the stimulation of PFC induces dream lucidity during REM sleep158 in lucid dreamers (see below). The demonstrated effectiveness of tDCS in activating PFC is theoretically relevant, as dream lucidity is accompanied by a shift in EEG power, especially in the 40 Hz range of frontal brain regions159. This is consistent with the finding that transcranial alternating current stimulation (tACS) in the lower gamma band during REM sleep influences the ongoing frontal brain activity 20

ACCEPTED MANUSCRIPT and induces self-reflective awareness in dreams160. Moreover, synchronous oscillations around 40 Hz of frontal regions are also present in lucid SOREMP dreams of narcoleptic patients161. Finally, tDCS also influences the neural substrates of mind-wandering: the propensity to mind-wander of subjects performing a monotonous task with a periodical sampling of their thoughts is enhanced by

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stimulation through an anode electrode on the left dlPFC and a cathode electrode on the right supraorbital area162.

Brain stimulation techniques may also cast light on the cognitive processes involved in dreamlike

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experiences. Indeed, an interhemispheric paired pulse transcranial magnetic stimulation (TMS) study showed a lower interhemispheric connectivity associated with REM sleep, suggesting a

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possible explanation for dream features like the lack of insight, time distortion, and amnesia163. Other techniques, such as magnetoencephalography (MEG), which allow a better localization of the regions where the signals originate164, could also be applied to identify the variations in the activity of specific brain regions subserving given dream features.

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In summary, multi-channel and intracranial recordings of brain activity have made possible more refined analyses of EEG signals, identifying specific patterns predictive of dream recall after awakening from REM and NREM sleep, the functioning of cortical and subcortical nuclei involved

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sleep stages.

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in memory processing, and the role played by specific brain structures stimulated during distinct

5. TOWARD AN INTEGRATIVE APPROACH TO DREAMING AND ITS NEURAL BASIS The neurophysiological signatures provided by the new methods of sleep recording and analysis allow accurate correspondences to be established between the characteristics of pre-awakening sleep and dream recall (and perhaps specific dream contents), thus overcoming some traditional methodological constraints of dream investigation, such as the much more tentative temporal location of dreaming (and thus the correspondence of its contents with PSG indicators) compared with goal-directed mental experiences in wakefulness. 21

ACCEPTED MANUSCRIPT Closer temporal proximities of physiological markers and dream contents may now be established by combining one or more of the new methods and the traditional paradigms of dream research. In particular, two poorly explored dimensions of dream contents, namely their voluntary control and behavioral enactment, promise important insights into the neural basis and the cognitive processes

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of dreaming. Indeed, previously agreed contents may be inserted by lucid dreamers into the ongoing dream experience in REM sleep159,160,165, and dream contents may be enacted during episodes of REM sleep behavior disorder (RBD) in patients with this parasomnia166,167.

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The finding that there is a greater level of reactivation of the cerebral regions involved in learning a new task in trained subjects than in controls during REM sleep112 and SWS168 suggests that such

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cerebral reactivation should also be accompanied by that of the task-related information. Pertinent evidence may be gathered by investigating lucid dreamers159,160,165, as they are aware of the ongoing “dreaming state” and capable of both performing predefined actions while all standard PSG criteria of REM sleep are fulfilled and sending previously agreed eye signals as temporal markers of their

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lucid state. Indeed, neuronal activation of the sensorimotor cortex during lucid REM dreaming (measured by fMRI and NIRS) appears comparable to that of a given movement (hand clenching), both imagined and performed in waking, by the same subjects159,160,169. This finding is important

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because EEG analyses have revealed increased gamma band activity over frontal and frontolateral areas in REM sleep, when the dream is lucid compared with when it is “nonlucid”159.

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Interestingly, “lucidity” is a dimension of dreaming that can be learnt159 or prompted by frontal low tACS in the lower gamma band160. A similar increase in gamma activity over frontal and frontolateral areas has also been observed in SOREMP of daytime naps in narcolepsy patients170, who often report being able to maintain or recover lucidity while dreaming and modify unpleasant or frightening dream contents161,170. It would also be of interest to establish whether the same cerebral areas are activated during different sleep stages, as well as in waking, when the incorporation of target information into dream content is triggered by an external stimulus previously associated with it (this paradigm being called 22

ACCEPTED MANUSCRIPT “cuing” or targeted memory reactivation: TMR171). This issue has been raised by some (indirect) evidence provided by TMR studies, showing that specific patterns of brain activity in the hippocampus and neocortex during wakefulness are reactivated during SWS and drive the consolidation of previously acquired information, for example, paired object-location associations

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(learnt while smelling a rose fragrance)172. An entwined crucial issue to be clarified is determining the capacity of the different sleep stages for memory replay, which is limited for such material as phrases of an artificial language173. Important insights may be expected from investigating whether:

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a) the effectiveness of cues for reactivation varies with respect to their perceptual modality (olfactory vs auditory172,174), in interaction with their associated information relevance (low/high

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value), and with respect to sleep as a whole, compared with wakefulness, where cues are always effective172, or to sleep stage; and b) the responsiveness of the brain structures activated by TMR differs in relation to the cues (for example, the modulation of the activity and connectivity of the parahippocampal cortex for spatial associations175).

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The possibility of identifying when specific visual contents are experienced has also been recently explored, in keeping with the assumptions of the so-called “brain reading” approach. This refers to the decoding of perceptual or mental conscious states by brain activity alone, using non-invasive

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techniques (for example, multivariate pattern analysis176) capable of decoding mental states with high accuracy and reasonable temporal resolution. By provoking repeated awakenings just after

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sleep onset and asking subjects to recall what they had seen, it has been found that fMRI patterns can be reliably linked, on a probabilistic basis, to the visual information (i.e., categories of objects such as cars, men or women) in dream reports177. It is apparent that, given the multimodal nature of dream contents (visual, auditory, tactile, etc.), much more complex pattern-recognition algorithms are required to decode information from different simultaneous modalities before attempting to extend “brain reading” to all dream features (that is, identifying the occurrence of contents with different perceptual features and their correlates in the activity of specific brain regions). However, the possibility of “brain reading” is also supported, in principle, by data collected with intracranial 23

ACCEPTED MANUSCRIPT EEG recordings across the medial temporal lobe and neocortex during sleep and wakefulness, and during visual stimulation with fixation178. Single neurons exhibit reduced firing rates before REMs and increasing rates immediately after REMs, similarly to the activity pattern upon image presentation during fixation in wakefulness. Furthermore, theta oscillations similarly reset following

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eye movements in sleep and wakefulness, as well as after visual stimulation.

The interpretative hypothesis that REMs during sleep rearrange discrete epochs of visual-like processing, as during wakefulness, is compatible with the findings of a study where the directions

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of REMs in RBD patients during dream enactment were matched with the description of dream content reported after awakening179. Moreover, the activity pattern of the motor cortex during

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phasic REM appears similar to that preceding a movement during wakefulness compared to tonic REM of the same motor cortex, and to the EEG activity pattern of dlPFC during both phasic and tonic REM sleep180.

A close correspondence between one or more PSG markers and specific contents of dream reports

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can also be established by observing video-PSG recordings of patients with RBD disorder. Indeed, external raters blindly analyzing video-PSG and dream reports181 can establish reliably whether dream contents, such as movements and vocalizations enacted during RBD episodes, correspond to

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those reported after awakening166. This means that some observed motor behaviors can be considered markers of the concomitant elaboration of specific REM dream contents, which thus

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become predictable before reporting. The observation of enacted contents also confirms that dreaming is actually developed by RBD patients who always fail to recall dreams after awakening182.

Moreover, the possibility that two or more RBD episodes may occur in the same period of REM sleep of patients with narcolepsy allows the tentative temporal localization not only of the enacted, but also of the intermediate contents, which reflect REM-sleep/wakefulness dissociative phenomena (for example, awareness of dream-state, volitional control of contents or out-of-body experiences)183. This, albeit limited, reconstruction of the time course of dreaming might, in turn, 24

ACCEPTED MANUSCRIPT facilitate the identification of specific EEG correlates of dissociative phenomena (such as prefrontal gamma activity for the awareness of dreaming-state159,161). To sum up, the use of multiple techniques of sleep recording allows an accurate operational approach to such complex issues as the temporal location of given contents (as made possible by

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comparing video-PSG recordings with verbal reports in the case of dream enactment in RBD episodes), as well as of episodes of lucid dreaming, and the replay of pre-sleep acquired information

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for incorporation into dream content.

6. CONCLUSION

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Taken together, the findings reviewed clearly indicate that the development of new PSG, videorecording and neuroimaging techniques has been an important step in the process of identifying the neural basis of dreaming. Indeed, their development has led to a more accurate assessment of the temporal location of dreaming during sleep and, possibly, to a clarification of the time course of

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specific contents, as well as of the factors responsible for the intra- and inter-individual variability in dream generation and recall. Moreover, the construction of general models of mental experience as a consciousness phenomenon of sleep and waking has generated more specific hypotheses on the

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neural basis of dreaming and guided the collection of reliable data for both mental activity and regional cerebral activity during PSG-defined sleep stages. Even if PSG and neuroimaging have

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seldom been combined to date, technical advances will lead to more accurate and pertinent questions as to the neural correlates of dreaming and its features. Finally, the use of neuroimaging techniques may strengthen the reliability of dream reports against some persistent skepticism1. Indeed, fMRI measurements have disclosed important differences in the activation of specific brain areas (right inferior frontal gyrus, right superior and middle temporal gyrus) when an actually experienced dream is recalled compared with one listened to or read in wakefulness or with a daytime mental activity184. The observation of these differences provides a strong argument supporting the reliability of dream reports and, overall, suggests a further strategy 25

ACCEPTED MANUSCRIPT for the investigation of both the inter-individual (HDR vs LDR) and intra-individual (success vs failure) differences in dream recall. There seems to be no doubt that the new techniques of sleep recordings, used on their own or combined with those of neuroimaging analysis of brain functioning, are yielding important new

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insights into how the brain generates dreams during sleep, as well as dreamlike experiences in waking. These insights converge to indicate that the continuity between the mental experiences elaborated in waking and sleep primarily manifests itself in terms of similarity in the functioning of

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the cognitive processes involved in their processing, rather than in the types or amount of memories

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transformed into dream contents2,5.

PRACTICE POINTS

A more or less dreamlike mental experience is reported after over 80% of awakenings from REM

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sleep and about 50% of awakenings from NREM sleep.

There is a large inter-individual (high/low recallers) and intra-individual variability (between stages and nights) in dream recall frequency and in perceptual and formal characteristics of dream

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experience.

Clinical studies on the success/failure of dream recall and on perceptual and formal characteristics of dream experience in patients with acute brain damage have documented that, overall, the

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temporoparieto-occipital junction and the ventromedial prefrontal cortex are involved in dreaming.

Neuroimaging studies have substantially confirmed clinical indications on the neural bases of dreaming and disclosed a certain parallelism between the functioning of specific brain structures in dreaming during sleep and daydreaming, mind-wandering and resting states in wakefulness.

Intracranial sleep recordings and high-density electroencephalography have provided new insights into dreaming during various sleep stages and “off-line” mental experiences in waking.

26

ACCEPTED MANUSCRIPT The new techniques of sleep recording and quantitative analysis of sleep have led to the development of new research strategies and the revitalization of traditional paradigms.

RESEARCH AGENDA

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The functioning of specific cognitive processes (e.g., activation of episodic and semantic information, access to associative networks, working memory) during various sleep stages and cycles compared to their functioning in wake should be established in detail.

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Investigation into the relations between dream generation and recall and EEG features of prior sleep should benefit from the evaluation of intracranial cortical and subcortical recordings.

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Trait-like (high/low recallers) and state-like (sleep stages/cycles) differences in dream recall should be further investigated using hd-EEG (and fMRI) techniques.

Comparison of the activation of frontal and temporal brain structures during the recall of actual dreams and listened to or read dreams and imagined events may elucidate the different recall

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strategies in high and low recallers.

Assessing the predictive power of theta EEG oscillations in frontal regions for dream generation and memory encoding during REM sleep of distinct cycles should be established to identify

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circadian variations in the frequency and characteristics of dream experience.

The correspondence of specific (motor or verbal) dream contents and their enactment in RBD

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episodes may allow the identification of both the temporal location during REM sleep of dissociated REM-sleep/wakefulness phenomena and facilitate the detection of EEG markers (such as gamma activity for dream lucidity).

The role of dreaming in the reprocessing and consolidation of memories should be investigated by combining SEEG techniques and targeted memory reactivation (i.e., cuing) during distinct sleep stages and cycles.

Conflict of interest All authors report no conflict of interest. 27

ACCEPTED MANUSCRIPT Acknowledgments This work was supported by grants from the Fondazione del Monte di Bologna e Ravenna to Carlo Cipolli (RF: 2012-2407) and from the Italian Ministry of Health (RF:2009-1528677) to Luigi De

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Gennaro. The authors are indebted to Cristina Marzano and Fabio Moroni for their comments on a preliminary version, to Alessandra Laffi for secretarial assistance and to an anonymous reviewer for

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many thorough comments and helpful suggestions.

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