Alice Laniepce

Najlaa Lahbairi

Nicolas Cabé

Anne-Lise Pitel

Dr Géraldine Rauchs
email: geraldine.rauchs@inserm.fr

CONTRIBUTION OF SLEEP DISTURBANCES TO THE HETEROGENEITY OF COGNITIVE AND BRAIN ALTERATIONS IN ALCOHOL USE DISORDER Running title: Sleep and alcohol-related brain structure and function

Keywords: Sleep disturbances, alcohol use disorder, cognition, brain, neuroimaging, relapse

Cognitive and brain alterations are common in alcohol use disorder and vary importantly from one patient to another. Sleep disturbances are also very frequent in these patients and remain largely neglected even though they can persist after drinking cessation. Sleep disturbances may be the consequence of specific brain alterations, resulting in cognitive impairments. But sleep disruption may also exacerbate alcohol-related brain abnormalities and cognitive deficits through common pathophysiological mechanisms. Besides, sleep disturbances seem a vulnerability factor for the development of alcohol use disorder. From a clinical perspective, sleep disturbances are known to affect treatment outcome and to increase the risk of relapse.

In this article, we conducted a narrative review to provide a better understanding of the relationships between sleep disturbances, brain and cognition in alcohol use disorder. We suggest that the heterogeneity of brain and cognitive alterations observed in patients with alcohol use disorder could at least partially be explained by associated sleep disturbances. We also believe that sleep disruption could indirectly favor relapse by exacerbating neuropsychological impairments required in psychosocial treatment and for the maintenance of abstinence. Implications for clinical practice as well as perspectives for future research are proposed.

INTRODUCTION

Alcohol is a widely promoted and consumed psychoactive substance that can lead to maladaptive patterns of use such as Alcohol Use Disorder (AUD). AUD is among the most prevalent mental disorders worldwide [START_REF] Carvalho | Alcohol use disorders[END_REF]. The 2018 World Health Organization's global status report on alcohol and health indicated that, in 2016, an estimated 283 million people had AUD (which represents 5.1% of adults aged 15 years and older in the world), with a large variation by countries and gender. Europe shows the highest prevalence (8.8% of the adult population) followed by the US (8.2% of the adult population), and the Western Pacific Region (4.7% of the adult population) and finally the lowest rate was found in the Eastern Mediterranean countries (0.8% of the same age population) [START_REF]Global status report on alcohol and health[END_REF].

AUD has significant personal, interpersonal, social and economic consequences and is associated with numerous physical and psychiatric comorbidities [START_REF] Rehm | The relationship between different dimensions of alcohol use and the burden of disease-an update[END_REF] leading to significant morbidity and mortality [START_REF] Connor | Alcohol use disorders[END_REF]. Despite all these considerable negative consequences, very few AUD patients seek treatment (20% of AUD patients in the US [START_REF] Grant | Epidemiology of DSM-5 Alcohol Use Disorder[END_REF]) potentially because of social stigma, consequences on personal life and employment of cognitive disabilities leading to lack of insight regarding their situation [START_REF] Berre | Emotional processing and social cognition in alcohol use disorder[END_REF]. Altered perception of these negative consequences may result from the harmful effects of AUD on brain structure and function.

Alcohol-related brain abnormalities are associated not only with neuropsychological impairments but also with sleep disturbances that, all together, result in increased risk of relapse.

While there have been other recent reviews on sleep in AUD [START_REF] Koob | Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework[END_REF][START_REF] Colrain | Alcohol and the sleeping brain[END_REF][START_REF] Chakravorty | Alcohol Dependence and Its Relationship With Insomnia and Other Sleep Disorders[END_REF], the specific objective of this synthetic narrative review is to address the relationships between sleep disturbances and brain structure and function in AUD. We aim at offering a novel perspective of the pathophysiology of alcohol-related brain damage and cognitive deficits by introducing sleep disturbances as a key factor. We will first review alcohol-related brain abnormalities, associated neuropsychological deficits and sleep alterations. Then, we will describe the relationships between sleep quality, and cognitive and brain alterations observed in AUD.

ALCOHOL-RELATED NEUROPSYCHOLOGICAL IMPAIRMENTS AND BRAIN

ABNORMALITIES

AUD is defined as "a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using". According to the DSM-5 [START_REF]DSM-5 Diagnostic Classification[END_REF], AUD ranges from mild to severe depending on the number of criteria (out of 11) met by patients. The presence of two or three criteria indicates mild AUD, four to five criteria suggest moderate AUD and more than six criteria defines severe AUD. AUD will be used throughout the article even though this term is relatively recent. Before 2013, "alcoholism" and later "alcohol dependence" or "alcohol abuse" were used as a diagnosis (with specific criteria for each) based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; [START_REF]Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition[END_REF]) or the £International Classification of Diseases [START_REF] Health Organization | Mental and behavioural disorders due to psychoactive substance use[END_REF].

Chronic and excessive alcohol consumption affects brain macrostructure and microstructure as well as cognition and motor abilities. These consequences of AUD have been recognized by the DSM-5 as mild or major "alcohol-induced neurocognitive disorders" depending on the severity of the impact on daily life and autonomy. Globally, three brain networks, involved in episodic memory, executive functions and emotion and social cognition, are particularly affected in AUD patients. In the following paragraphs, we will describe how the gray matter (GM) nodes and white matter (WM) connections of these three brain circuits are altered in AUD patients, in absence of alcohol-related neurological complications such as Korsakoff's syndrome. We will also depict associated neuropsychological deficits observed in 50 to 80% of AUD patients [START_REF] Oscar-Berman | Alcohol: Effects on neurobehavioral functions and the brain[END_REF].

Episodic memory network

Episodic memory deficits are observed in AUD patients, affecting learning, encoding, and retrieval abilities [START_REF] Pitel | Genuine episodic memory deficits and executive dysfunctions in alcoholic subjects early in abstinence[END_REF][START_REF] Noël | The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism[END_REF]. Moreover, patients had impaired recall of temporal and spatial context of encoding [START_REF] Pitel | Genuine episodic memory deficits and executive dysfunctions in alcoholic subjects early in abstinence[END_REF][START_REF] Noël | The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism[END_REF][START_REF] Pitel | Episodic and Working Memory Deficits in Alcoholic Korsakoff Patients: The Continuity Theory Revisited[END_REF] as well as deficits of autonoetic consciousness, which gives a subject the conscious feeling of travelling in time to relive the original event or to project into the future [START_REF] Pitel | Genuine episodic memory deficits and executive dysfunctions in alcoholic subjects early in abstinence[END_REF][START_REF] Noël | The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism[END_REF]. These episodic memory impairments have been described as genuine as they do not seem to be exclusively explained by executive dysfunction [START_REF] Pitel | Genuine episodic memory deficits and executive dysfunctions in alcoholic subjects early in abstinence[END_REF][START_REF] Noël | The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism[END_REF]. The Papez circuit (PC) [START_REF] Papez | A proposed mechanism of emotion[END_REF], involved in episodic memory functioning, includes the hippocampal formation, which connects to the mammillary bodies via the fornix. The thalamus then receives information from the mammillary bodies via the mammillothalamic tract. The anterior limb of the internal capsule connects the thalamus to the cingulate gyrus, which is in turn connected back to the hippocampus through the cingulum bundle.

Shrinkage of the GM nodes of the PC have repeatedly been found in AUD patients, with volume deficits in the hippocampus [START_REF] Wilson | Problematic alcohol use and reduced hippocampal volume: a meta-analytic review[END_REF], mammillary bodies [START_REF] Sullivan | In vivo mammillary body volume deficits in amnesic and nonamnesic alcoholics[END_REF][START_REF] Pitel | Macrostructural abnormalities in Korsakoff syndrome compared with uncomplicated alcoholism[END_REF] and cingulate cortex [START_REF] Klaming | Shared gray matter reductions across alcohol use disorder and posttraumatic stress disorder in the anterior cingulate cortex: A dual meta-analysis[END_REF]. Structural abnormalities have also been demonstrated in the thalamus of AUD patients [START_REF] Pitel | Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction[END_REF] and more particularly a disconnection between the hippocampus and the anterior thalamic nuclei [START_REF] Segobin | Dissociating thalamic alterations in alcohol use disorder defines specificity of Korsakoff's syndrome[END_REF]. Altered WM fibers were found in the cingulum, fornix and anterior thalamic radiation [START_REF] Segobin | Integrity of white matter microstructure in alcoholics with and without Korsakoff's syndrome[END_REF]. Several studies explored brain-function relationships within the PC of AUD patients. Reduced hippocampal volume was reported in AUD patients without episodic memory deficits, suggesting that hippocampal shrinkage itself cannot explain alcohol-related episodic memory impairments [START_REF] Sullivan | Anterior Hippocampal Volume Deficits in Nonamnesic, Aging Chronic Alcoholics[END_REF]. When considering brain microstructure, low episodic memory performance was associated with altered parahippocampal GM [START_REF] Chanraud | Episodic Memory in Detoxified Alcoholics: Contribution of Grey Matter Microstructure Alteration[END_REF] and WM integrity in the fornix and cingulum bundle [START_REF] Segobin | Integrity of white matter microstructure in alcoholics with and without Korsakoff's syndrome[END_REF].

Executive functions and motor network

Executive dysfunction has been considered as the most frequent cognitive impairment among AUD patients [START_REF] Ihara | Group and case study of the dysexecutive syndrome in alcoholism without amnesia[END_REF], including flexibility, updating, planning, and inhibition deficits [START_REF] Berre | Alcohol Use Disorder Permanent and Transient Effects on the Brain and Neuropsychological Functions[END_REF]. AUD patients also exhibit impaired decision making abilities [START_REF] Berre | Alcohol Use Disorder Permanent and Transient Effects on the Brain and Neuropsychological Functions[END_REF].

Executive deficits have been associated with damage of the fronto-cerebellar circuit (FCC). The FCC consists of two parallel closed loops within the cortico-thalamo-cerebellar circuitry: one executive and one motor [START_REF] Kelly | Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate[END_REF]. The frontal cortex (dorsolateral prefrontal cortex for the executive loop, motor cortex for the motor loop) is connected to the pons via corticopontine tracts and back to the cerebellum (crus I and II for the executive loop, lobules IV-VI of the vermis) through the middle cerebellar peduncle. Then, the superior cerebellar peduncle connects the cerebellum to the thalamus, which is linked to the frontal cortex through the anterior limb of the internal capsule and the anterior corona radiata.

Studies have reached consensus regarding the significant and prominent damage of the frontal cortex and cerebellum in AUD patients [START_REF] Zahr | Perspectives on fronto-fugal circuitry from human imaging of alcohol use disorders[END_REF]. In addition, macrostructural WM alterations have been observed in the pons, cerebellum and midbrain [START_REF] Sullivan | Compromised pontocerebellar and cerebellothalamocortical systems: Speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism[END_REF][START_REF] Chanraud | Brain Morphometry and Cognitive Performance in Detoxified Alcohol-Dependents with Preserved Psychosocial Functioning[END_REF]. Structural connectivity within the FCC is also affected with altered WM microstructure in the anterior limb of the internal capsule, the anterior corona radiata, middle and superior cerebellar peduncles [START_REF] Segobin | Integrity of white matter microstructure in alcoholics with and without Korsakoff's syndrome[END_REF] and fibers connecting the midbrain to the pons [START_REF] Chanraud | Diffusion Tensor Tractography in Mesencephalic Bundles: Relation to Mental Flexibility in Detoxified Alcohol-Dependent Subjects[END_REF].

Executive deficits observed in AUD were first related to frontal lobe damage [START_REF] Zahr | Perspectives on fronto-fugal circuitry from human imaging of alcohol use disorders[END_REF].

More recent investigations highlighted that alterations of other nodes of the FCC may be better predictors of executive dysfunction than damage of the prefrontal cortex [START_REF] Sullivan | Compromised pontocerebellar and cerebellothalamocortical systems: Speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism[END_REF][START_REF] Zahr | Contributions of studies on alcohol use disorders to understanding cerebellar function[END_REF].

Executive deficits were related to shrinkage of the pons, thalamus and cerebellum [START_REF] Sullivan | Compromised pontocerebellar and cerebellothalamocortical systems: Speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism[END_REF][START_REF] Chanraud | Diffusion Tensor Tractography in Mesencephalic Bundles: Relation to Mental Flexibility in Detoxified Alcohol-Dependent Subjects[END_REF] as well as to the number of WM fibers between the midbrain and the pons [START_REF] Chanraud | Diffusion Tensor Tractography in Mesencephalic Bundles: Relation to Mental Flexibility in Detoxified Alcohol-Dependent Subjects[END_REF]. In a combined MRI-DTI study, Crespi et al. [START_REF] Crespi | Executive Impairment in Alcohol Use Disorder Reflects Structural Changes in Large-Scale Brain Networks: A Joint Independent Component Analysis on Gray-Matter and White-Matter Features[END_REF] found that executive performance correlated with GM volume and DTI measures of key nodes and fiber tracts of the salience, default-mode and central executive networks

Social cognition network

Social cognition refers to the processes contributing to the perception and understanding of social environments and interactions [START_REF] Frith | Social cognition[END_REF]. It includes several abilities that enable an individual to behave appropriately in a social context or environment: the ability to decode emotions, empathy, and the Theory of Mind (ToM). Empathy refers to the ability to understand and experience what others feel without confusion between oneself and others.

ToM refers to the ability to attribute mental (cognitive and affective) states to oneself and others. The social cognition network encompasses three circuits [START_REF] Abu-Akel | Neuroanatomical and neurochemical bases of theory of mind[END_REF]. The cognitive ToM circuit is mediated by the medial and dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, superior temporal sulcus, temporoparietal junction, and temporal poles [START_REF] Dvash | Theory of Mind and Empathy as Multidimensional Constructs[END_REF]. The affective ToM (i.e., cognitive empathy) involves the ventromedial prefrontal cortex, temporoparietal junction, and precuneus. Finally, the affective empathy network is mediated by the inferior frontal gyrus, anterior cingulate cortex, amygdala, and insula.

Structural brain alterations in the frontal cortex have been described in the previous section. Temporal cortices are also affected, as well as the amygdala and insula [START_REF] Yang | Cortical and subcortical gray matter shrinkage in alcohol-use disorders: a voxel-based meta-analysis[END_REF][START_REF] Mackey | Mega-analysis of gray matter volume in substance dependence: General and substance-specific regional effects[END_REF]. As summarized in a recent narrative review [START_REF] Berre | Emotional processing and social cognition in alcohol use disorder[END_REF], different emotional and social cognition impairments have been described in AUD: altered abilities to express emotions and to decode emotions on faces, in prosody, body postures, and music. Empathy and ToM abilities are also affected [9 for a review].

Very few studies examined the relationship between social cognition and brain structure in AUD. Trick et al. [START_REF] Trick | Impaired fear recognition and attentional set-shifting is associated with brain structural changes in alcoholic patients[END_REF] found smaller GM volume in the inferior frontal cortex and insula in AUD patients with low fear recognition performance. Affective empathy was related to cortical thinning in the inferior frontal gyrus [START_REF] Schmidt | Cortical thickness and trait empathy in patients and people at high risk for alcohol use disorders[END_REF].

Heterogeneity of brain abnormalities and neuropsychological impairments among AUD patients

AUD is characterized by a marked variability between patients in the nature and extent of brain abnormalities and neuropsychological deficits [START_REF] Ihara | Group and case study of the dysexecutive syndrome in alcoholism without amnesia[END_REF]. Several factors were identified to explain this variability such as parameters related to alcohol history [START_REF] Sullivan | Pattern of motor and cognitive deficits in detoxified alcoholic men[END_REF][START_REF] Ryback | The continuum and specificity of the effects of alcohol on memory. A review[END_REF][START_REF] Zinn | Executive functioning early in abstinence from alcohol[END_REF][START_REF] Beatty | Neuropsychological Deficits in Sober Alcoholics: Influences of Chronicity and Recent Alcohol Consumption[END_REF], or associated malnutrition, thiamine deficiency [START_REF] Coulbault | Thiamine and phosphate esters concentrations in whole blood and serum of patients with alcohol use disorder: a relation with cognitive deficits[END_REF][START_REF] Pitel | Signs of preclinical wernicke's encephalopathy and thiamine levels as predictors of neuropsychological deficits in alcoholism without korsakoff's syndrome[END_REF][START_REF] Ritz | Clinical and Biological Risk Factors for Neuropsychological Impairment in Alcohol Use Disorder[END_REF] and liver dysfunction [START_REF] Ritz | Clinical and Biological Risk Factors for Neuropsychological Impairment in Alcohol Use Disorder[END_REF]. Sleep quality is another factor that could contribute to the heterogeneity of altered brain structure and function in AUD. Indeed, many studies showed that sleep is essential for efficient cognitive abilities [START_REF] Lowe | The neurocognitive consequences of sleep restriction: A meta-analytic review[END_REF] and is related to brain integrity [START_REF] Sexton | Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults[END_REF][START_REF] Sexton | Associations between self-reported sleep quality and white matter in communitydwelling older adults: A prospective cohort study[END_REF], and there is a considerable evidence that AUD is frequently associated with disturbed sleep.

ALCOHOL-INDUCED SLEEP ABNORMALITIES

Described as alcohol-induced sleep disorder in the DSM-IV and the DSM-5, sleep disturbances can manifest at each stage of AUD, from active alcohol use to sustained abstinence. We will describe, in this section, the nature of sleep complaint and objective sleep disturbances reported during periods of active alcohol use, acute alcohol withdrawal, early abstinence and late abstinence (respectively 1 to 2 weeks, 2 to 8 weeks and more than 8 weeks after drinking cessation; [START_REF] Brower | Alcohol's effects on sleep in alcoholics[END_REF]; Figure 1).

During active alcohol use

Using the Insomnia Severity Index [START_REF] Bastien | Validation of the Insomnia Severity Index as an outcome measure for insomnia research[END_REF], [START_REF] Chaudhary | Insomnia in alcohol dependent subjects is associated with greater psychosocial problem severity[END_REF] reported insomnia symptoms in 74% of AUD patients [START_REF] Chaudhary | Insomnia in alcohol dependent subjects is associated with greater psychosocial problem severity[END_REF]. Patients actively consuming alcohol complained of difficulties falling asleep (i.e., longer sleep latency; [START_REF] Skoloda | Sleep quality reported by drinking and nondrinking alcoholics[END_REF] as well as fragmented sleep [START_REF] Hodges | The effects of acute alcohol withdrawal on sleep[END_REF].

Recent studies using the Pittsburgh Sleep Quality index (PSQI [START_REF] Buysse | The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research[END_REF]) revealed that sleep disturbances are very frequent at this stage of AUD (> 70% of AUD patients [START_REF] Hodges | The effects of acute alcohol withdrawal on sleep[END_REF][START_REF] Neu | The Effect of Detoxification on Sleep: How Does Sleep Quality Change during Qualified Detoxification Treatment?[END_REF]), independently of age, sex and duration of alcohol dependency [START_REF] Neu | The Effect of Detoxification on Sleep: How Does Sleep Quality Change during Qualified Detoxification Treatment?[END_REF]. All the dimensions of sleep explored in the PSQI (subjective sleep quality, sleep latency and duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, daytime dysfunction) are affected [START_REF] Hodges | The effects of acute alcohol withdrawal on sleep[END_REF]. The PSQI score during active drinking predicted sleep disturbances after two weeks of detoxification [START_REF] Neu | The Effect of Detoxification on Sleep: How Does Sleep Quality Change during Qualified Detoxification Treatment?[END_REF]. Mello and Mendelson reported that active alcohol use induces sleep fragmentation, which is not associated with a decrease in TST. In addition, patients also experience daytime sleepiness combined with occasional naps [START_REF] Mello | Behavioral studies of sleep patterns in alcoholics during intoxication and withdrawal[END_REF]. Sleepiness would concern about one-third of AUD patients [START_REF] Hodges | The effects of acute alcohol withdrawal on sleep[END_REF].

Polysomnography (PSG) studies conducted at this stage of AUD are scarce but revealed substantial changes in sleep architecture. Thus, sleep onset latency (SOL) and REM sleep latency are increased. Total sleep time (TST) is generally decreased (but see [START_REF] Allen | Slow wave sleep: A predictor of individual differences in response to drinking?[END_REF] for different results). The amount of slow wave sleep (SWS) increases while time spent in REM sleep is reduced [START_REF] Gross | Experimental study of sleep in chronic alcoholics before, during, and after four days of heavy drinking with a nondrinking comparison[END_REF][START_REF] Gross | The relation between baseline slow wave sleep and the slow wave sleep response to alcohol in alcoholics[END_REF][START_REF] Wagman | Effects of alcohol ingestion and abstinence on slow wave sleep of alcoholics[END_REF].

During acute alcohol withdrawal

Drinking cessation is associated in about 50% of AUD patients with clinical symptoms that constitute the alcohol withdrawal syndrome (AWS [START_REF] Schuckit | Alcohol-use disorders[END_REF]). The severity of AWS is variable, ranging from a mild clinical form to a more severe one with seizures or delirium tremens potentially leading to death [66]. AWS results from a brain hyperexcitability due to increased glutamate transmission combined with decreased GABA transmission [66]. Sleep disturbances are mainly reported during the first week of drinking cessation, in more than 90% of AUD patients assessed with the PSQI [START_REF] Cohn | Sequential studies of sleep disturbance and quality of life in abstaining alcoholics[END_REF][START_REF] Steinig | Perception of sleep and dreams in alcoholdependent patients during detoxication and abstinence[END_REF]. These subjective sleep disturbances have been confirmed by actigraphy and PSG recordings. More precisely, studies revealed the persistence of decreased TST [START_REF] Lahti | The impacts of nitrous oxide gas on sleep quality during alcohol withdrawal[END_REF] and sleep efficiency [START_REF] Hodges | The effects of acute alcohol withdrawal on sleep[END_REF], and increased SOL. The amount of SWS decreases [START_REF] Johnson | Sleep During Alcohol Intake and Withdrawal in the Chronic Alcoholic[END_REF], associated with higher sleep fragmentation [START_REF] Hodges | The effects of acute alcohol withdrawal on sleep[END_REF][START_REF] Lahti | The impacts of nitrous oxide gas on sleep quality during alcohol withdrawal[END_REF][START_REF] Johnson | Sleep During Alcohol Intake and Withdrawal in the Chronic Alcoholic[END_REF]. Of note, the proportion of REM sleep, which was reduced during active alcohol consumption, increases during the withdrawal phase. This phenomenon, called REM sleep rebound [START_REF] Mello | Behavioral studies of sleep patterns in alcoholics during intoxication and withdrawal[END_REF][START_REF] Johnson | Sleep During Alcohol Intake and Withdrawal in the Chronic Alcoholic[END_REF][START_REF] Allen | Recovery time for alcoholics after prolonged alcohol intoxication[END_REF][START_REF] Stein | Disturbed sleep and its relationship to alcohol use[END_REF], results from an increase in the number of REM episodes and shorter intervals in between. The severity of sleep disturbances during this phase varies importantly across patients, depending on the severity of AWS [START_REF] Lahti | The impacts of nitrous oxide gas on sleep quality during alcohol withdrawal[END_REF], the history of previous severe neurological complications related to withdrawal (such as delirium tremens; [START_REF] Greenberg | Delirium tremens and dreaming[END_REF][START_REF] Kotorii | Terminal sleep following delirium tremens in chronic alcoholics -polysomnographic and behavioral study[END_REF][START_REF] Nakazawa | Polysomnographic study of terminal sleep following delirium tremens[END_REF]) or even the global health and nutritional status of the patient [START_REF] Landolt | Sleep abnormalities during abstinence in alcohol-dependent patients. Aetiology and management[END_REF].

Early in abstinence

Once the acute signs of withdrawal have disappeared and benzodiazepines prescribed during withdrawal no longer affect brain and cognition, AUD patients are generally referred as "early in abstinence" until about 8 weeks of abstinence [START_REF] Chakravorty | Alcohol Dependence and Its Relationship With Insomnia and Other Sleep Disorders[END_REF]. Numerous studies have been conducted during this phase and indicate that patients still complain about their sleep [START_REF] Neu | The Effect of Detoxification on Sleep: How Does Sleep Quality Change during Qualified Detoxification Treatment?[END_REF][START_REF] Cohn | Sequential studies of sleep disturbance and quality of life in abstaining alcoholics[END_REF][START_REF] Steinig | Perception of sleep and dreams in alcoholdependent patients during detoxication and abstinence[END_REF][START_REF] Gann | Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence[END_REF][START_REF] Irwin | Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep[END_REF][START_REF] Junghanns | Chronic and high alcohol consumption has a negative impact on sleep and sleep-associated consolidation of declarative memory[END_REF][START_REF] Kolla | The course of sleep disturbances in early alcohol recovery: An observational cohort study[END_REF][START_REF] Perney | Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis[END_REF][START_REF] Wallen | The Prevalence of Sleep Disturbance in Alcoholics Admitted for Treatment[END_REF][START_REF] Brower | Polysomnographic and subjective sleep predictors of alcoholic relapse[END_REF][START_REF] Chakravorty | Covariates of Craving in Actively Drinking Alcoholics[END_REF][START_REF] Colrain | The Impact of Alcoholism on Sleep Evoked Δ Frequency Responses[END_REF][START_REF] Currie | Comprehensive assessment of insomnia in recovering alcoholics using daily sleep diaries and ambulatory monitoring[END_REF][START_REF] De Zambotti | Poor autonomic nervous system functioning during sleep in recently detoxified alcoholdependent men and women[END_REF][START_REF] Feige | Sleep Electroencephalographic Spectral Power After Withdrawal from Alcohol in Alcohol-Dependent Patients[END_REF][START_REF] Foster | Impaired sleep in alcohol misusers and dependent alcoholics and the impact upon outcome[END_REF]. They mainly complain of difficulties falling asleep, numerous nocturnal awakenings, decreased TST and daytime sleepiness [START_REF] Chakravorty | Alcohol Dependence and Its Relationship With Insomnia and Other Sleep Disorders[END_REF]. Insomnia symptoms are very common in patients, being reported in 36 to 72% of them [START_REF] Brower | Alcohol's effects on sleep in alcoholics[END_REF]. This variability can be explained by methodological issues such as different AUD diagnosis criteria, duration of abstinence, sleep measures or contexts in which the assessment was done (in a clinical setting or at home) [START_REF] Stein | Disturbed sleep and its relationship to alcohol use[END_REF].

Even if it is a little bit out of the scope of this review, it is important to mention that cognitive deficits are not prominent in non AUD insomnia patients. The studies have provided inconsistent findings that can be explained by methodological differences, the definition of the insomnia group and the tasks used that may not be sufficiently sensitive to reveal subtle deficits [START_REF] Brownlow | Insomnia and Cognitive Performance[END_REF]. A meta-analysis showed that individuals with insomnia exhibit deficits in manipulation and retention in working memory, episodic memory and problem solving, these impairments being of small to mediate magnitude [START_REF] Fortier-Brochu | Insomnia and daytime cognitive performance: A meta-analysis[END_REF]. In another meta-analysis focusing on executive functions, insomnia patients were impaired on reaction time-based tasks assessing inhibitory control and mental flexibility [START_REF] Ballesio | Executive Functions in Insomnia Disorder: A Systematic Review and Exploratory Meta-Analysis[END_REF]. Insomnia-related cognitive deficits appear to be observed in tasks relying to some extent on the integrity of the prefrontal cortex. In the case of AUD, we can surmise that insomnia symptoms do not induce major cognitive impairments, but rather exacerbate alcohol-related deficits.

Despite an improvement in sleep quality during the first month of abstinence (in particular, decreased SOL and increased TST), PSG studies revealed that AUD patients early in abstinence still exhibit longer SOL and poorer sleep efficiency than controls after drinking cessation [START_REF] Gann | Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence[END_REF][START_REF] Feige | Sleep Electroencephalographic Spectral Power After Withdrawal from Alcohol in Alcohol-Dependent Patients[END_REF][START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF][START_REF] Gann | Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression[END_REF][START_REF] Gillin | EEG sleep studies in "pure" primary alcoholism during subacute withdrawal: Relationships to normal controls, age, and other clinical variables[END_REF][START_REF] Irwin | Polysomnographic and Spectral Sleep EEG in Primary Alcoholics: An Interaction Between Alcohol Dependence and African-American Ethnicity[END_REF][START_REF] Bon | Sleep in detoxified alcoholics: impairment of most standard sleep parameters and increased risk for sleep apnea, but not for myoclonias--a controlled study[END_REF][START_REF] Singh | Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients[END_REF][START_REF] Snyder | Sleep patterns of sober chronic alcoholics[END_REF]. In addition, such sleep changes are not systematically reported. SOL and SE did not differ from controls in the following studies [START_REF] Irwin | Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep[END_REF][START_REF] De Zambotti | Poor autonomic nervous system functioning during sleep in recently detoxified alcoholdependent men and women[END_REF][START_REF] Irwin | Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics[END_REF], while Brower et al.

found that only SOL was in the normal range [START_REF] Brower | Sleep homeostasis in alcohol-dependent, depressed and healthy control men[END_REF].. Sleep is also more fragmented, due to nocturnal awakenings, increased time spent awake and numerous stage shifts [START_REF] Koob | Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework[END_REF]. Most of the studies reported significant changes in NREM sleep [START_REF] Koob | Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework[END_REF], including a decrease in time spent in N2 and N3 sleep [START_REF] Irwin | Polysomnographic and Spectral Sleep EEG in Primary Alcoholics: An Interaction Between Alcohol Dependence and African-American Ethnicity[END_REF][START_REF] Snyder | Sleep patterns of sober chronic alcoholics[END_REF][START_REF] Irwin | Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics[END_REF][START_REF] Brower | Sleep homeostasis in alcohol-dependent, depressed and healthy control men[END_REF], contrasting with an increase in lighter N1 sleep [START_REF] Gann | Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence[END_REF][START_REF] Irwin | Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep[END_REF][START_REF] De Zambotti | Poor autonomic nervous system functioning during sleep in recently detoxified alcoholdependent men and women[END_REF][START_REF] Feige | Sleep Electroencephalographic Spectral Power After Withdrawal from Alcohol in Alcohol-Dependent Patients[END_REF][START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF][START_REF] Gann | Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression[END_REF][START_REF] Gillin | EEG sleep studies in "pure" primary alcoholism during subacute withdrawal: Relationships to normal controls, age, and other clinical variables[END_REF][START_REF] Irwin | Polysomnographic and Spectral Sleep EEG in Primary Alcoholics: An Interaction Between Alcohol Dependence and African-American Ethnicity[END_REF][START_REF] Singh | Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients[END_REF][START_REF] Irwin | Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics[END_REF]. Compared to controls, EEG analyses showed lower delta activity in N1-N2 [START_REF] Singh | Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients[END_REF] and N3 sleep [START_REF] Irwin | Polysomnographic and Spectral Sleep EEG in Primary Alcoholics: An Interaction Between Alcohol Dependence and African-American Ethnicity[END_REF][START_REF] Singh | Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients[END_REF], supported by visual observation of lower amplitude of K-complexes (evoked delta waves) [START_REF] Colrain | The Impact of Alcoholism on Sleep Evoked Δ Frequency Responses[END_REF][START_REF] Willoughby | Partial K-Complex Recovery Following Short-Term Abstinence in Individuals with Alcohol Use Disorder[END_REF]. Changes in REM sleep appear less consistent. Indeed, some studies reported an increase of about 10% in REM sleep proportion related to shorter REM latency [START_REF] Koob | Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework[END_REF][START_REF] Johnson | Sleep During Alcohol Intake and Withdrawal in the Chronic Alcoholic[END_REF][START_REF] Irwin | Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep[END_REF][START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF][START_REF] Irwin | Polysomnographic and Spectral Sleep EEG in Primary Alcoholics: An Interaction Between Alcohol Dependence and African-American Ethnicity[END_REF][START_REF] Irwin | Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics[END_REF][START_REF] Williams | Altered Sleep Physiology in Chronic Alcoholics: Reversal with Abstinence[END_REF], an increase in the number of REM sleep episodes and a shorter interval in between [START_REF] Gann | Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence[END_REF][START_REF] Feige | Sleep Electroencephalographic Spectral Power After Withdrawal from Alcohol in Alcohol-Dependent Patients[END_REF][START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF][START_REF] Irwin | Polysomnographic and Spectral Sleep EEG in Primary Alcoholics: An Interaction Between Alcohol Dependence and African-American Ethnicity[END_REF][START_REF] Brower | Sleep homeostasis in alcohol-dependent, depressed and healthy control men[END_REF]. An increase in beta activity during REM sleep was also reported [START_REF] Singh | Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients[END_REF]. On the contrary, other studies did not observe any change in REM sleep [START_REF] De Zambotti | Poor autonomic nervous system functioning during sleep in recently detoxified alcoholdependent men and women[END_REF][START_REF] Bon | Sleep in detoxified alcoholics: impairment of most standard sleep parameters and increased risk for sleep apnea, but not for myoclonias--a controlled study[END_REF][START_REF] Snyder | Sleep patterns of sober chronic alcoholics[END_REF]. These heterogeneous findings could be explained by the presence of psychiatric comorbidities such as depressive symptoms [START_REF] Irwin | Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep[END_REF][START_REF] Gillin | Increased Pressure for Rapid Eye Movement Sleep at Time of Hospital Admission Predicts Relapse in Nondepressed Patients With Primary Alcoholism at 3-Month Follow-up[END_REF].

Late in abstinence

Sleep disturbances may persist for a considerable period of time after drinking cessation. The perception of sleep quality remains significantly poorer compared to healthy controls after 3 months [START_REF] Cohn | Sequential studies of sleep disturbance and quality of life in abstaining alcoholics[END_REF][START_REF] Junghanns | Chronic and high alcohol consumption has a negative impact on sleep and sleep-associated consolidation of declarative memory[END_REF][START_REF] Foster | Impaired sleep in alcohol misusers and dependent alcoholics and the impact upon outcome[END_REF], 6 months [START_REF] Gann | Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence[END_REF][START_REF] Perney | Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis[END_REF] or even one year of abstinence [START_REF] Currie | Comprehensive assessment of insomnia in recovering alcoholics using daily sleep diaries and ambulatory monitoring[END_REF]. The significant improvement of insomnia symptoms during the first six months is explained by drinking cessation (55% of the variance explained ; [START_REF] Perney | Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis[END_REF]) but is also observed with a reduction of alcohol consumption [START_REF] Brower | Persistent Insomnia, Abstinence, and Moderate Drinking in Alcohol-Dependent Individuals[END_REF].

Longitudinal PSG studies confirmed the persistence of all sleep disturbances listed above. Increased SOL, decreased TST as well as SWS and REM sleep stages abnormalities are still observed in late abstinence. Lower slow wave activity was reported in NREM sleep, especially over frontal derivations [START_REF] Colrain | The Impact of Alcoholism on Sleep Evoked Δ Frequency Responses[END_REF]. Difficulties falling asleep (reflected by longer SOL) tend to disappear 5 to 9 months after drinking cessation, while sleep fragmentation seems to persist during 21 months, and TST to normalize within 2 years [START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF][START_REF] Williams | Altered Sleep Physiology in Chronic Alcoholics: Reversal with Abstinence[END_REF]. SWS progressively reaches normal amounts by 2 years of sobriety [START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF][START_REF] Williams | Altered Sleep Physiology in Chronic Alcoholics: Reversal with Abstinence[END_REF]. Regarding REM sleep, here again findings diverge across studies. Drummond et al. reported that, after 27 months of abstinence, most of sleep measures recovered within the normal range, except the proportion of REM sleep which was still higher an REM sleep latency which remained shorter in AUD patients compared to controls [START_REF] Drummond | The Sleep of Abstinent Pure Primary Alcoholic Patients: Natural Course and Relationship to Relapse[END_REF]. By contrast, other data indicate that after only 3 months of abstinence, REM sleep returns to normal values, and others did not find any significant differences in REM sleep when comparing patients to healthy controls [START_REF] Williams | Altered Sleep Physiology in Chronic Alcoholics: Reversal with Abstinence[END_REF][START_REF] Schiavi | Chronic alcoholism and male sexual function[END_REF][START_REF] Vitiello | Sleep, alcohol and alcohol abuse[END_REF]. These inconsistencies in the dynamic of sleep recovery may be explained by differences in patients' characteristics and the duration of sobriety.

Other sleep disturbances in AUD

Besides changes in sleep quality and architecture, AUD patients also frequently suffer from sleep-disordered breathing (SDB) and periodic limb movement disorder (PLMD) that can both contribute to alter sleep quality. We will also briefly describe alterations in circadian rhythms.

A recent meta-analysis showed that alcohol consumption is a risk factor for the development or worsening of SDB [START_REF] Kolla | The impact of alcohol on breathing parameters during sleep: A systematic review and metaanalysis[END_REF]. Few investigations have been conducted on SDB in recently detoxified AUD patients. In a study carried out in 188 AUD patients, a moderate SDB (defined as 10 or more apneas-hypopneas per hour of sleep) was observed in 23,5% of patients aged 40 or over and 50% of patients aged 60 or over [START_REF] Aldrich | Sleep-disordered breathing in alcoholics[END_REF]. Respiratory events are both central [START_REF] Tan | Sleep apnoea in alcoholic patients after withdrawal[END_REF] and obstructive [START_REF] Bon | Sleep in detoxified alcoholics: impairment of most standard sleep parameters and increased risk for sleep apnea, but not for myoclonias--a controlled study[END_REF][START_REF] Aldrich | Sleep-disordered breathing in alcoholics[END_REF][START_REF] Tan | Sleep apnoea in alcoholic patients after withdrawal[END_REF]. Several hypotheses have been proposed to explain the high prevalence of SDB in AUD patients. First, alcohol consumption reduces genioglossal muscle tone, favoring upper airway collapse [START_REF] Aldrich | Sleep-disordered breathing in alcoholics[END_REF]. Second, excessive alcohol consumption represents an important caloric intake, that may lead on the long-term to overweight or obesity, which are known as risk factors for SDB [111]. Finally, alcohol has neurotoxic effects on the brain stem and vagus nerve that are involved in respiratory functions [START_REF] Vitiello | Sleep, alcohol and alcohol abuse[END_REF].

PLMD is diagnosed when a patient meets the criterion of 15 repetitive limb movements per hour of sleep. The prevalence of PLMD in the general population is 3.9% [START_REF] Ohayon | Prevalence of restless legs syndrome and periodic limb movement disorder in the general population[END_REF]. Alcohol use has been shown to increase the frequency of periodic limb movements (PLMs; [START_REF] Aldrich | Sleep-disordered breathing in alcoholics: association with age[END_REF]) but, to the best of our knowledge, there is no prevalence estimation in AUD patients. Two studies observed more PLMs in AUD patients compared to controls [START_REF] Schiavi | Chronic alcoholism and male sexual function[END_REF][START_REF] Gann | Periodic limb movements during sleep in alcohol dependent patients[END_REF] but this result was not consistently reported [START_REF] Bon | Sleep in detoxified alcoholics: impairment of most standard sleep parameters and increased risk for sleep apnea, but not for myoclonias--a controlled study[END_REF]. In a study conducted in 139 AUD patients, Brower & Hall [START_REF] Brower | Effects of age and alcoholism on sleep: a controlled study[END_REF] showed that AUD patients, and especially those aged over 55, had more may be explained by a decrease in dopaminergic neurotransmission [START_REF] Gann | Periodic limb movements during sleep in alcohol dependent patients[END_REF].

Finally, alterations of circadian rhythms are also common in AUD (see [START_REF] Meyrel | Alterations in circadian rhythms following alcohol use: A systematic review[END_REF] for a recent review). Briefly, acute alcohol intake induces dose-dependent changes in biological rhythms (e.g., core body temperature, melatonin and cortisol secretions) but these changes normalize within 24 hours. In AUD patients, because of chronic alcohol use, those changes are more severe and persist over time. During acute alcohol withdrawal, the desynchronization of circadian rhythms correlates with the severity of AWS and is associated with neurological complications. With abstinence, alterations of circadian rhythms generally recover within one month, except for melatonin secretion whose disruption can last several months [START_REF] Meyrel | Alterations in circadian rhythms following alcohol use: A systematic review[END_REF].

IMPACT OF SLEEP DISTURBANCES ON COGNITIVE IMPAIRMENTS IN AUD

The role of sleep in cognitive and emotional functioning has been well described in healthy individuals [START_REF] Rauchs | The relationships between memory systems and sleep stages[END_REF][START_REF] Walker | Overnight therapy? The role of sleep in emotional brain processing[END_REF] and accumulating evidence suggests that sleep disturbances are associated with cognitive deficits in ageing [START_REF] Yaffe | Connections between sleep and cognition in older adults[END_REF], Alzheimer's disease [START_REF] Peter-Derex | Sleep and Alzheimer's disease[END_REF] and in psychiatric diseases such as schizophrenia [START_REF] Winsky-Sommerer | Disturbances of sleep quality, timing and structure and their relationship with other neuropsychiatric symptoms in Alzheimer's disease and schizophrenia: Insights from studies in patient populations and animal models[END_REF]. However, the impact of sleep disturbances on cognitive deficits in AUD remains unclear. In this section, we will focus on episodic memory, executive functions, emotion and social cognition, which are known to be frequently impaired in AUD patients as previously mentioned (Table 1).

Sleep and episodic memory

One of the essential functions of sleep is to favor the consolidation of recently acquired information into long-term stores [START_REF] Diekelmann | The memory function of sleep[END_REF][START_REF] Harand | How Aging Affects Sleep-Dependent Memory Consolidation?[END_REF]. For episodic memories, this process mainly operates during NREM sleep [START_REF] Diekelmann | The memory function of sleep[END_REF], but some studies also reported a beneficial effect of REM sleep [START_REF] Rauchs | Consolidation of Strictly Episodic Memories Mainly Requires Rapid Eye Movement Sleep[END_REF], especially for emotionally-laden memories [START_REF] Wagner | Emotional Memory Formation Is Enhanced across Sleep 9[END_REF].

To our knowledge, only one study investigated sleep-dependent memory consolidation in AUD patients [START_REF] Junghanns | Chronic and high alcohol consumption has a negative impact on sleep and sleep-associated consolidation of declarative memory[END_REF]. The authors proposed a face-name association task to two groups of patients with different lengths of abstinence (short-term (2-4 weeks) and long-term (10-22 weeks) abstinence). In both groups of patients, daily alcohol consumption before drinking cessation negatively correlated with memory performance, and the duration of alcohol dependence negatively correlated with the amount of NREM sleep. The two groups did not differ from each other with respect to sleep parameters and presented similar overnight decline in recall performance. In the group of long-term abstainers, the duration of abstinence positively correlated with the amount of SWS. The authors concluded that chronic and excessive alcohol consumption negatively affects NREM sleep, which in turn impairs sleepdependent memory consolidation. In this study, patients also performed a mirror tracing task to assess procedural memory consolidation. Both groups improved significantly their performance with practice. The overnight improvement in mirror tracing performance negatively correlated with SOL and positively correlated with the amount of REM sleep.

Compared to normative data, AUD patients showed higher amount of REM sleep [START_REF] Junghanns | Chronic and high alcohol consumption has a negative impact on sleep and sleep-associated consolidation of declarative memory[END_REF], but this may not be pathological, as increases in REM sleep were observed after procedural learning [START_REF] Smith | Posttraining increases in REM sleep intensity implicate REM sleep in memory processing and provide a biological marker of learning potential[END_REF]. Overall, sleep-dependent memory consolidation has been seldom investigated in recently sober AUD patients. Even though the available data suggest a dissociation between episodic and procedural memory consolidation, the former being impaired and the latter one rather preserved, further studies are needed to confirm these results.

Beyond its contribution to overnight memory consolidation, poor sleep before learning has a negative impact on new learning. Yoo et al. [START_REF] Yoo | A deficit in the ability to form new human memories without sleep[END_REF] showed that one single night of sleep deprivation reduces hippocampal activity during encoding and modifies functional connectivity in alertness networks, compromising successful encoding of new experiences. A similar phenomenon was also described after multiple nights of partial sleep restriction [START_REF] Cousins | Memory encoding is impaired after multiple nights of partial sleep restriction[END_REF] and in individuals reporting short sleep duration [START_REF] Lowe | The neurocognitive consequences of sleep restriction: A meta-analytic review[END_REF]. No study has been conducted in AUD patients, but these results suggest that poor sleep may also have an impact on patients' encoding abilities.

Sleep and executive functions

Executive functions are particularly vulnerable to poor sleep quality [START_REF] Benitez | Poor sleep quality diminishes cognitive functioning independent of depression and anxiety in healthy young adults[END_REF], total sleep deprivation and chronic sleep restriction [START_REF] Lowe | The neurocognitive consequences of sleep restriction: A meta-analytic review[END_REF] in young and middle-aged individuals. Sleep deprivation impairs flexibility [START_REF] Lim | A meta-analysis of the impact of short-term sleep deprivation on cognitive variables[END_REF], inhibition (by increasing perseverations, errors, omissions and the sensibility to interference [START_REF] Lowe | The neurocognitive consequences of sleep restriction: A meta-analytic review[END_REF]) and working memory [START_REF] Ferrarelli | An increase in sleep slow waves predicts better working memory performance in healthy individuals[END_REF]. Sleep duration has an inverse U shaped relationship with executive functions: short and very long sleep durations are associated with lower working memory and mental flexibility performance in young individuals [START_REF] Wilckens | The role of non-rapid eye movement slow-wave activity in prefrontal metabolism across young and middle-aged adults[END_REF][START_REF] Van Oostrom | Long sleep 52 duration is associated with lower cognitive function among middle-age adults -the Doetinchem Cohort Study[END_REF]. Beyond sleep quantity, impaired sleep continuity (reflected by increased time spent awake after sleep onset) and lower proportion of SWS also have a 20 negative impact on working memory performance [START_REF] Ferrarelli | An increase in sleep slow waves predicts better working memory performance in healthy individuals[END_REF][START_REF] Wilckens | The role of non-rapid eye movement slow-wave activity in prefrontal metabolism across young and middle-aged adults[END_REF]. In addition, sleep is essential for decision making, which requires the integration of complex cognitive and emotional information. Sleep deprivation impairs decision making [START_REF] Killgore | Impaired decision making following 49 h of sleep deprivation[END_REF], favors risk taking [START_REF] Killgore | Impaired decision making following 49 h of sleep deprivation[END_REF], and increases impulsivity [START_REF] Anderson | Sleep deprivation lowers inhibition and enhances impulsivity to negative stimuli[END_REF]. Indeed, total sleep deprivation may alter the functioning of brain areas involved in the reward network, which in turn may favor unrealistic expectations of gains and underestimation of the consequences of losses [START_REF] Venkatraman | Sleep Deprivation Elevates Expectation of Gains and Attenuates Response to Losses Following Risky Decisions[END_REF]. Concerning the impact of sleep restriction, results are less clear. Although some studies showed that sleep restriction impairs decision making abilities [START_REF] Womack | Sleep Loss and Risk-Taking Behavior: A Review of the Literature[END_REF][START_REF] Maric | Insufficient sleep: Enhanced risk-seeking relates to low local sleep intensity[END_REF], a meta-analysis concluded that evidence in favor of a negative impact of chronic sleep restriction on risk taking is insufficient [START_REF] Lowe | The neurocognitive consequences of sleep restriction: A meta-analytic review[END_REF]. Finally, Seeley et al. [START_REF] Seeley | Ventromedial prefrontal theta activity during rapid eye movement sleep is associated with improved decision-making on the Iowa Gambling Task[END_REF] proposed trials of the Iowa Gambling Tasks prior and after a period of sleep and showed that post-learning sleep, especially theta activity during REM sleep, enhanced decision-making performance.

The impact of sleep disturbances on the executive deficits frequently observed in AUD was explored in only one study reporting that the amount of REM sleep positively correlated with performance on a backward span task, suggesting a relationship between REM sleep and the ability to manipulate information in working memory [START_REF] Benson | REM sleep time and digit span impairment in alcoholics[END_REF]. Two hypotheses were proposed to explain these results. First, chronic and excessive alcohol consumption alters REM sleep, which in turn impairs the processes underlying the central executive of working memory. Second, chronic and excessive alcohol consumption disrupts common neurobiological mechanisms involved in both sleep and working memory.

A recent study combined an assessment of subjective sleep quality using the PSQI, with cognitive testing and a neuroimaging examination in a sample of AUD patients with and without Korsakoff's Syndrome (KS). The authors found that only the AUD patients who did not complain about their sleep presented executive deficits, similar to those of KS patients who did not complain either [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF]. These results suggest that certain cognitive deficits, especially executive dysfunction, may alter the ability to self-evaluate sleep quality. From a clinical perspective, sleep problems could be neglected in AUD patients who are not cognitively able to complain and would therefore remain untreated. Such a situation would worsen sleep-related consequences in AUD patients, and affect the treatment outcome.

Sleep, emotion and social cognition

In healthy individuals, chronic sleep restriction and total sleep deprivation impair the ability to decode emotional expressions, especially anger [START_REF] Van Der Helm | Sleep Deprivation Impairs the Accurate Recognition of Human Emotions[END_REF], happiness [START_REF] Van Der Helm | Sleep Deprivation Impairs the Accurate Recognition of Human Emotions[END_REF][START_REF] Killgore | Sleep deprivation impairs recognition of specific emotions[END_REF] and sadness [START_REF] Killgore | Sleep deprivation impairs recognition of specific emotions[END_REF][START_REF] Macdonald | Sleep physiology predicts memory retention after reactivation[END_REF]. In addition, total sleep deprivation [START_REF] Guadagni | The effects of sleep deprivation on emotional empathy[END_REF], lower subjective sleep quality [START_REF] Guadagni | Sleep quality and its association with the insular cortex in emotional empathy[END_REF], and shorter sleep duration [START_REF] Guadagni | Sleep quality and its association with the insular cortex in emotional empathy[END_REF] alter the ability to infer the emotional state of other individuals (affective ToM). Sleep deprivation has also been related to more stereotyping and implicit bias toward minority groups, influencing social decision made about individual's trustworthiness based on facial features [START_REF] Alkozei | Chronic sleep restriction affects the association between implicit bias and explicit social decision making[END_REF][START_REF] Alkozei | Chronic Sleep Restriction Increases Negative Implicit Attitudes Toward Arab Muslims[END_REF]. Finally, poor sleepers are more susceptible to social rejection and conflicting relationships, contributing to social withdrawal and loneliness.

Overall, these studies highlight the links between poor sleep and impaired social cognition abilities, which could accentuate social issues and interpersonal difficulties frequently observed in AUD patients [START_REF] Berre | Emotional processing and social cognition in alcohol use disorder[END_REF]. Complaining about sleep is associated with more severe subjective reports of alcohol-related psychosocial problems in AUD [START_REF] Chaudhary | Insomnia in alcohol dependent subjects is associated with greater psychosocial problem severity[END_REF][START_REF] Kolla | Sleep disturbances in early alcohol recovery: Prevalence and associations with clinical characteristics and severity of alcohol consumption[END_REF].

However, no study has investigated the potential moderation effect of sleep disturbances on the relationships between AUD and impaired emotional and social cognition. Finally, social difficulties (loneliness, interpersonal conflicts, perceived social rejection) also have an impact on both subjective and objective sleep quality, suggesting a potential bidirectional relationships between sleep disturbances and interpersonal problems [START_REF] Gordon | The Social Side of Sleep: Elucidating the Links Between Sleep and Social Processes[END_REF].

To sum up, only a few studies have explored the links between sleep alterations and cognitive and emotional impairments in AUD patients. First, these studies show that sleepdependent episodic memory consolidation is impaired and associated with the amount of SWS. In contrast, consolidation in procedural memory appears as preserved [START_REF] Junghanns | Chronic and high alcohol consumption has a negative impact on sleep and sleep-associated consolidation of declarative memory[END_REF]. Second, executive deficits are related to low amounts of REM sleep [START_REF] Benson | REM sleep time and digit span impairment in alcoholics[END_REF] and an altered ability to self-evaluate sleep quality leading to rare or mild sleep complaint in those patients [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF].

Finally, greater self-reported psychosocial problems are associated with major sleep complaints [START_REF] Chaudhary | Insomnia in alcohol dependent subjects is associated with greater psychosocial problem severity[END_REF][START_REF] Kolla | Sleep disturbances in early alcohol recovery: Prevalence and associations with clinical characteristics and severity of alcohol consumption[END_REF]. Further studies are now required to deepen our understanding regarding the role of the different sleep components/parameters on cognitive and emotional deficits and to determine whether these associations last with sustained abstinence.

RELATIONSHIPS BETWEEN SLEEP DISTURBANCES AND BRAIN

ALTERATIONS IN AUD

Considering the relationships between sleep disturbances and cognitive impairments, it is relevant to investigate how sleep is related to structural (including GM and WM volume)

and functional brain alterations in AUD patients.

Structural brain imaging

Cross-sectional studies conducted in middle-aged individuals revealed that poor selfreported sleep quality [START_REF] Sexton | Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults[END_REF], early morning awakening [START_REF] Stoffers | Orbitofrontal Gray Matter Relates to Early Morning Awakening: A Neural Correlate of Insomnia Complaints?[END_REF] and daytime sleepiness [START_REF] Killgore | Voxel-based morphometric gray matter correlates of daytime sleepiness[END_REF] are associated with lower GM volume in frontal areas. In addition, short sleep duration was related to global atrophy [START_REF] Lo | Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance[END_REF], to lower thalamic volume [START_REF] Liu | Long-term total sleep deprivation reduces thalamic gray matter volume in healthy men[END_REF] and to altered white matter microstructure in frontal areas, superior corona radiata and the inferior longitudinal fasciculus [START_REF] Khalsa | Habitual sleep durations and subjective sleep quality predict white matter differences in the human brain[END_REF]. In addition, the presence of subjective sleep disturbances correlated with reduced white matter integrity in frontal, anterior cingulate and limbic regions as well as in the insula [START_REF] Khalsa | Habitual sleep durations and subjective sleep quality predict white matter differences in the human brain[END_REF] but see [START_REF] Kocevska | Sleep complaints and cerebral white matter: A prospective bidirectional study[END_REF] for different results).

Three studies investigated the association between sleep abnormalities and structural brain alterations in abstinent AUD patients. Using a descriptive analysis of 9 AUD patients, Ishibadi et al. [START_REF] Ishibashi | Cerebral atrophy and slow wave sleep of abstinent chronic alcoholics[END_REF] showed that with prolonged abstinence, a recovery of structural damage measured with computerized tomography (CT) scans was observed in 5 patients, four of them also presenting an increase in the amount of SWS. The authors concluded that early in abstinence, low amounts of SWS may result from cortical atrophy. In a more recent study, Colrain et al. [START_REF] Colrain | Independent Contributions of Cortical Gray Matter, Aging, Sex and Alcoholism to K-Complex Amplitude Evoked During Sleep[END_REF] showed that lower regional GM volumes (in frontal, temporal, sensorimotor, parietal and occipital cortices) contributed to the changes in the amplitude of Kcomplexes observed in long-term abstinent AUD patients. Regarding subjective sleep quality, a relationship was found between subjective sleep disturbances and brain structure: only the AUD patients who did not complain about their sleep presented brain shrinkage and altered white matter integrity in fronto-temporal regions and in the thalamus. These brain alterations were as severe as those observed in KS patients who did not complain either [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF]. Such findings reinforce the idea that preserved brain integrity is required to be able to efficiently self-evaluate sleep quality.

Functional brain imaging

Sleep disturbances are also associated with changes in brain metabolism and functional connectivity in healthy individuals. In young to middle-aged adults, a decrease of the metabolic activity in the frontal cortex, anterior cingulate gyrus, thalamus, basal ganglia and cerebellum has been described following sleep deprivation [START_REF] Thomas | Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity[END_REF]. Moreover, several brain regions constituting the default mode network, the limbic, salience and executive networks are functionally altered following sleep deprivation [START_REF] Simon | Tired and misconnected: A breakdown of brain modularity following sleep deprivation[END_REF]. Changes in functional connectivity have been commonly reported after sleep deprivation, notably between the thalamus and middle temporal regions, superior and medial frontal areas, and anterior cingulate cortex [START_REF] Krause | The sleep-deprived human brain[END_REF]. In particular, functional changes in frontal and anterior cingulate areas induced by sleep deprivation have been related to executive deficits [START_REF] Killgore | Effects of sleep deprivation on cognition[END_REF]. When exposed to emotional faces, sleep-deprived subjects exhibited higher amygdala activation and lower activity in the prefrontal cortex compared to individuals who slept normally, resulting in a prefrontalamygdala disconnection [START_REF] Yoo | The human emotional brain without sleep -a prefrontal amygdala disconnect[END_REF]. Moreover, sleep-deprived individuals exhibited lower activity in the ToM network (including the temporo-parietal junction, the precuneus and the medial prefrontal cortex) associated with higher subjective rating of loneliness [START_REF] Simon | Sleep loss causes social withdrawal and loneliness[END_REF].

Poor sleep quality may thus contribute to the changes in brain metabolism and functional connectivity reported in AUD patients. However, studies conducted on that topic are scarce. Only a recent investigation showed that the severity of AUD was associated with poor subjective sleep quality, this association being mediated by the strength of the functional connectivity between the thalamus and the medial prefrontal cortex in AUD patients [START_REF] Liu | Reduced resting-state functional 56 connectivity and sleep impairment in abstinent male alcohol-dependent patients[END_REF].

However, patients were asked to stop drinking for at least 48 hours before inclusion, which may have directly altered sleep and modified functional brain connectivity through potential AWS.

To sum up, sleep disturbances appear to be associated with structural and functional brain alterations in abstinent AUD patients. While the number of studies is too limited to draw definite conclusions, integrity of fronto-temporal regions and thalamus may be related to sleep quality in this disease [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF][START_REF] Liu | Reduced resting-state functional 56 connectivity and sleep impairment in abstinent male alcohol-dependent patients[END_REF]. Previous studies differ in terms of inclusion criteria, sleep parameters analyzed and neuroimaging approaches used. Further studies are thus needed to specify the brain regions that are particularly vulnerable to poor sleep quality in AUD using multimodal neuroimaging (brain structure, metabolism and functional connectivity), and to determine whether recovery occurs with sustained abstinence.

DISCUSSION

Overall, very few studies have explored the relationships between sleep quality, brain alterations and cognitive deficits in AUD patients. Regarding sleep complaint, subjective sleep quality was associated with both structural [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF] and functional brain alterations [START_REF] Liu | Reduced resting-state functional 56 connectivity and sleep impairment in abstinent male alcohol-dependent patients[END_REF],

notably in fronto-temporal regions and the thalamus. Subjective sleep disturbances were also related to poor executive abilities [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF] and more severe interpersonal difficulties [START_REF] Chaudhary | Insomnia in alcohol dependent subjects is associated with greater psychosocial problem severity[END_REF][START_REF] Kolla | Sleep disturbances in early alcohol recovery: Prevalence and associations with clinical characteristics and severity of alcohol consumption[END_REF].

Regarding objective sleep quality, the decrease in SWS was associated with structural brain alterations [START_REF] Ishibashi | Cerebral atrophy and slow wave sleep of abstinent chronic alcoholics[END_REF] and impaired episodic memory consolidation [START_REF] Junghanns | Chronic and high alcohol consumption has a negative impact on sleep and sleep-associated consolidation of declarative memory[END_REF]. In contrast, low amounts of REM sleep were rather related to executive deficits [START_REF] Benson | REM sleep time and digit span impairment in alcoholics[END_REF]. While further studies are required to confirm these relationships, these data suggest that both subjective and objective sleep quality correlate with alcohol-related brain damage and cognitive deficits in AUD patients. Below, we discuss the directionality of these relationships and their time course, as well as their potential role in alcohol relapse (Figure 2).

• Sleep disturbances and alcohol-related brain damage: bidirectional relationships?

A crucial question concerns the directionality of the relationships between sleep disturbances, and alcohol-related brain abnormalities and dysfunction in AUD. We propose that two complementary hypotheses may explain these bidirectional relationships (❶, Figure 2). First, sleep disturbances may be a consequence of alcohol-related brain damage. Both chronic and excessive alcohol consumption, as well as alcohol withdrawal, induce brain damage in sleep-promoting regions. Structural and/or functional abnormalities in frontal temporal and parietal cortices, as well as in the thalamus and the insula [START_REF] Dubé | Cortical Thinning Explains Changes in Sleep Slow Waves during Adulthood[END_REF][START_REF] Latreille | Age-related cortical signatures of human sleep electroencephalography[END_REF][START_REF] Mander | Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging[END_REF] may contribute to sleep disturbances, which may in turn result in cognitive deficits in AUD patients. Second, poor sleep quality may contribute to the development of alcohol-related brain damage. Alcohol-related sleep disturbances and brain damage may co-occur since resulting from common mechanisms such as impaired neurogenesis [START_REF] Fernandes | Detrimental role of prolonged sleep deprivation on adult neurogenesis[END_REF], increased glutamate levels [START_REF] Cortese | Regionspecific alteration in brain glutamate: Possible relationship to risk-taking behavior[END_REF][START_REF] Dash | Long-Term Homeostasis of Extracellular Glutamate in the Rat Cerebral Cortex across Sleep and Waking States[END_REF], neuroinflammation [START_REF] Irwin | Sleep disturbance, sleep duration, and inflammation: A systematic review and meta-analysis of cohort studies and experimental sleep deprivation[END_REF] and oxidative stress [START_REF] Villafuerte | Sleep Deprivation and Oxidative Stress in Animal Models: A Systematic Review[END_REF]. Brain abnormalities and cognitive deficits would thus be exacerbated in AUD patients with poor sleep quality. These two hypotheses seem difficult to disentangle in clinical studies and require preclinical investigations to be put to the test. However, exploration of sleep quality in the course of the disease may provide some first insights.

• Contribution of sleep disturbances at all stages of AUD

Sleep disturbances are present at all stages of AUD i.e. during acute alcohol intoxication, the acute alcohol withdrawal phase, as well as early and late in abstinence (❷, Figure 2). Several studies indicated that sleep disruption may even precede the development of AUD. Retrospective investigations showed that some AUD patients report sleep disruption before the onset of the disease [START_REF] Currie | Comprehensive assessment of insomnia in recovering alcoholics using daily sleep diaries and ambulatory monitoring[END_REF]. Moreover, studies conducted in adolescents [START_REF] Miller | Impulsive personality traits and alcohol use: Does sleeping help with thinking?[END_REF][START_REF] Hasler | Sleep and circadian contributions to adolescent alcohol use disorder[END_REF] and young adults [START_REF] Chung | Risk Factors Related to Binge Drinking[END_REF][START_REF] Popovici | Binge drinking and sleep problems among young adults[END_REF] suggest that difficulties in initiating and maintaining sleep may favour excessive alcohol consumption and binge drinking. Finally, the disruption of circadian rhythms may also be a factor contributing to the development of addictive behaviors [START_REF] Meyrel | Alterations in circadian rhythms following alcohol use: A systematic review[END_REF]. In particular, the evening chronotype has been associated with a higher risk of developing AUD [START_REF] Meyrel | Alterations in circadian rhythms following alcohol use: A systematic review[END_REF]. These results first suggest that sleep disturbances may be considered as an early vulnerability factor for substance abuse [START_REF] Hasler | Sleep and circadian risk factors for alcohol problems: a brief overview and proposed mechanisms[END_REF] and notably AUD. In addition, alcohol-related brain abnormalities and cognitive deficits tend to recover [START_REF] Perry | Cognitive Decline and Recovery in Alcohol Abuse[END_REF], at least partially, with sustained abstinence while sleep quality remains poor even in long-term abstainers. It will be relevant, in future studies, to understand how sleep could modulate cerebral and cognitive recovery, and whether poor sleep quality could explain, at least partly, the persistence of some cognitive deficits despite sobriety. Long-lasting sleep difficulties may thus contribute to persisting functional and structural brain abnormalities in AUD.

• Direct and indirect role of sleep disturbances in relapse

Previous studies demonstrated that sleep disturbances constitute a poor prognostic for treatment outcomes in AUD patients, by directly increasing the risk of alcohol relapse [START_REF] Brower | Insomnia, alcoholism and relapse[END_REF].

An association was observed between relapse and sleep disruption assessed using both questionnaires (global sleep complaint and difficulty to fall asleep) and objective measures (longer SOL, number of awakenings, increased REM sleep pressure, higher beta activity during REM sleep and decreased amount of NREM sleep; increased PLMs-arousal index)

[

. More recently, some authors proposed that sleep disturbances may indirectly contribute to relapse notably by increasing psycho-affective symptoms [START_REF] Gann | Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression[END_REF] and alcohol craving [START_REF] Chakravorty | Covariates of Craving in Actively Drinking Alcoholics[END_REF][START_REF] He | The Relationship between Alcohol Craving and Insomnia Symptoms in Alcohol-Dependent Individuals[END_REF]. Psycho-affective symptoms, such as anxiety and depression, often co-occur in AUD [START_REF] Mchugh | Alcohol Use Disorder and Depressive Disorders[END_REF][START_REF] Grant | Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions[END_REF] and increase the risk of relapse [START_REF] Hasin | Effects of Major Depression on Remission and Relapse of Substance Dependence[END_REF]. In AUD, sleep disturbances, and more particularly REM sleep abnormalities have been associated with more severe depressive symptoms [START_REF] Irwin | Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep[END_REF][START_REF] Gillin | Increased Pressure for Rapid Eye Movement Sleep at Time of Hospital Admission Predicts Relapse in Nondepressed Patients With Primary Alcoholism at 3-Month Follow-up[END_REF] and relapse [START_REF] Gann | Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence[END_REF][START_REF] Brower | Polysomnographic and subjective sleep predictors of alcoholic relapse[END_REF]. We can thus hypothesize an association between sleep disturbances, psycho-affective symptoms and relapse.

Craving, defined as the persistent urge or desire to use a substance [START_REF]DSM-5 Diagnostic Classification[END_REF], is experienced by 54-72% of AUD patients [START_REF] Chakravorty | Covariates of Craving in Actively Drinking Alcoholics[END_REF]. Some studies reported that a higher alcohol craving score (assessed using the Penn Alcohol Craving Scale, [START_REF] Flannery | Psychometric properties of the Penn Alcohol Craving Scale[END_REF] ) was related to difficulties falling asleep in recently detoxified AUD patients [START_REF] Chakravorty | Covariates of Craving in Actively Drinking Alcoholics[END_REF][START_REF] He | The Relationship between Alcohol Craving and Insomnia Symptoms in Alcohol-Dependent Individuals[END_REF] but also after 3 months of abstinence [START_REF] He | The Relationship between Alcohol Craving and Insomnia Symptoms in Alcohol-Dependent Individuals[END_REF]. Different hypotheses have been proposed to explain this relationship. At first, during the acute alcohol intoxication, many AUD patients use alcohol as a coping strategy to treat their sleep problems [START_REF] Kolla | The course of sleep disturbances in early alcohol recovery: An observational cohort study[END_REF][START_REF] Brower | Insomnia, Self-Medication, and Relapse to Alcoholism[END_REF][START_REF] Brooks | A Mixed Methods Examination of Sleep Throughout the Alcohol Recovery Process Grounded in the Social Cognitive Theory: The Role of Self-Efficacy and Craving[END_REF]. With prolonged alcohol consumption, the initially helpful effect of alcohol to fall sleep is reduced, due to a progressive tolerance to this hypnotic effect, leading to increased sleep disturbances, fatigue and/or negative mood state. These alterations, together an ineffective coping response to sleep problems or positive expectancies about the effects of alcohol on sleep, may in turn increase their urge to drink [START_REF] He | The Relationship between Alcohol Craving and Insomnia Symptoms in Alcohol-Dependent Individuals[END_REF]. Other mechanisms have been reported, notably the existence of common neurobiological substrates between sleep-wake regulation [START_REF] Sutcliffe | The hypocretins: Setting the arousal threshold[END_REF] and the modulation of alcohol consumption by regions involved in the reward system [START_REF] Valentino | Drugs, sleep, and the addicted brain[END_REF]. Further studies are needed to clarify the interactions between sleep, psycho-affective symptoms and craving in the context of alcohol relapse but their coexistence suggests the clinical relevance to manage them simultaneously.

Here, we propose that alcohol-related sleep disturbances may also indirectly increase the risk of alcohol relapse through their contribution to brain alterations and cognitive deficits (❸, Figure 2). In this review, we highlighted the fact that alcohol-related sleep alterations are associated with structural and functional abnormalities mainly in fronto-temporal regions and their connections, as well as in the thalamus. These brain regions, involved in several brain networks underlying episodic memory, executive functions, emotion and social cognition, are commonly damaged in recently detoxified AUD patients and such cognitive deficits are consequently frequently observed. Altered episodic memory abilities, executive function or social cognition could have negative consequences on patients' capacity to benefit fully from treatment [START_REF] Fein | Cognitive impairments in abstinent alcoholics[END_REF] or to maintain abstinence or reduce alcohol consumption. Indeed, psychosocial treatments, including cognitive-behavioral therapies or motivational interview, require these cognitive abilities [START_REF] Berre | Alcohol Use Disorder Permanent and Transient Effects on the Brain and Neuropsychological Functions[END_REF]. When they decide to change drinking behavior, patients must plan new strategies, inhibit old routines and make the right decision in risky situations.

From a clinical perspective, improving sleep quality should thus not only be considered as a therapeutic target to directly reduce alcohol craving and psycho-affective symptoms, but also to improve brain structure and function, which would indirectly favor treatment outcome.

Overall, sleep quality seems 1) to constitute a critical factor for the development of AUD, 2) to be a consequence of alcohol-related brain damage, 3) to contribute to the development of alcohol-related brain damage and cognitive deficits, and 4) to affect alcohol treatment outcome. It is thus crucial to manage sleep disturbances in AUD patients.

MANAGEMENT OF SLEEP DISORDERS IN AUD

Clinical observation and questioning of the patient are fundamental to reveal and characterize sleep difficulties. Identifying the nature of sleep complaint (difficulties falling asleep, early morning awakening, daytime sleepiness…) is essential to propose adapted intervention strategies and to avoid the use of alcohol as self-medication. In addition, it is of utmost importance to interpret sleep complaint in the light of the cognitive deficits of the patients, especially when those patients present severe executive dysfunction that may alter their self-evaluation abilities [START_REF] Laniepce | Neuropsychological and Neuroimaging Examinations of Self-Reported Sleep Quality in Alcohol Use Disorder With and Without Korsakoff's Syndrome[END_REF]. Sleep quality should be assessed in a dynamic way, at each step of the patients' management, to determine the origin of sleep disturbances and when they began. Indeed, a particular attention should be provided to AUD patients who used alcohol as a coping strategy for sleep problems because it may be associated with high risk of craving and subsequent relapse [START_REF] He | The Relationship between Alcohol Craving and Insomnia Symptoms in Alcohol-Dependent Individuals[END_REF].

In this way, treatment of sleep disturbances requires therapeutic options that result in both rapid and lasting sleep improvements. The very first strategy to improve sleep quality must systematically be to favor alcohol drinking cessation [START_REF] Perney | Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis[END_REF]. Non-pharmacological sleep interventions can be used from the acute withdrawal period to long-term sobriety.

Psychoeducation on sleep hygiene, aiming notably at identifying and correcting the false beliefs about sleep and about the effect of alcohol on sleep, is generally a good starting point but is not sufficient per se. Cognitive behavioral therapies can be conducted in case of persistent insomnia (CBT-I; [START_REF] Schutte-Rodin | Clinical guideline for the evaluation and management of chronic insomnia in adults[END_REF]). This kind of therapy has been successfully used in AUD patients [START_REF] Chakravorty | Alcohol Dependence and Its Relationship With Insomnia and Other Sleep Disorders[END_REF]. CBT programs require experienced staff, potentially limiting their application in clinical settings, and their efficacy is observed after several weeks of therapy. However, studies assessing internet-based [START_REF] Ritterband | Efficacy of an internet-based behavioral intervention for adults with insomnia[END_REF][START_REF] Espie | A randomized, placebo-controlled trial of online cognitive behavioral therapy for chronic insomnia disorder delivered via an automated media-rich web application[END_REF][START_REF] Zachariae | Efficacy of internet-delivered cognitive-behavioral therapy for insomnia -A systematic review and meta-analysis of randomized controlled trials[END_REF] and app-based [START_REF] Horsch | Mobile Phone-Delivered Cognitive Behavioral Therapy for Insomnia: A Randomized Waitlist Controlled Trial[END_REF] versions of CBT-1 revealed similar efficacity to more traditional therapy. Thus, these tools could be a relevant option in the treatment of insomnia. In parallel, a short-term prescription of pharmacological agents could also be proposed to promote a rapid sleep improvement in AUD patients with severe sleep difficulties [START_REF] Geoffroy | Management of insomnia in alcohol use disorder[END_REF]. For instance, a 12 week treatment by Gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, has been shown to improve the rate of abstinence and reduced the number of heavy drinking days in AUD patients. The treatment also improved mood, sleep disturbances and craving [START_REF] Mason | Gabapentin treatment for alcohol dependence a randomized clinical trial[END_REF]. However, a recent meta-analysis of 16 studies indicated that the effect on mood and sleep are not consistently observed [START_REF] Cheng | Gabapentinoids for treatment of alcohol use disorder: A systematic review and meta-analysis[END_REF]. Physical activity may also have a beneficial effect on sleep both in the general population and in patients with psychiatric diseases [START_REF] Kredlow | The effects of physical activity on sleep: a meta-analytic review[END_REF][START_REF] Lederman | Does exercise improve sleep quality in individuals with mental illness? A systematic review and meta-analysis[END_REF]. Thus, the development of physical activity programs, adjusted to patients' comorbidities, may be useful to improve sleep, but also cognitive abilities and quality of life, in AUD patients.

A persisting sleep complaint and/or the observation of daytime symptoms such as fatigue or excessive daytime sleepiness, may be signs of sleep disturbances and especially sleep apneas. Complementary examinations should be proposed to those patients to confirm the presence of sleep apneas and treat them (for instance with continuous positive airway pressure). Finally, it is also crucial to take psychiatric and other addictive comorbidities into account for the treatment of sleep disorders. These comorbidities could exacerbate existing sleep difficulties. For example, nicotine substitutes should be proposed in smoking AUD patients to reduce the effects of nicotine withdrawal overnight (i.e., multiple awakenings contributing to sleep fragmentation, [START_REF] Garcia | Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review[END_REF]).

CONCLUSION AND FUTURE DIRECTIONS

To sum up, alcohol-related sleep disturbances are present at all stages of AUD, can persist several months after drinking cessation and predict relapse. They can also be observed before the onset of AUD, favoring the emergence of substance abuse. In AUD patients early in abstinence, sleep disturbances seem to be related to altered structure and function of brain networks underlying episodic memory, executive functions, emotions and social cognition.

Sleep disturbances may rather precede the development of AUD than be a consequence of alcohol-related brain damage, and may thus contribute to the pathophysiology of AUD. The understanding of the interactions between sleep disturbances, cognitive deficits and brain alterations in AUD is still in its infancy. Studies combining sleep assessments, multimodal neuroimaging examinations (structural MRI, brain metabolism and functional connectivity) and fine-grained cognitive measures will undoubtedly improve our knowledge of this disease, favor the development of adapted treatment strategies and limit the risk of relapse. Abbreviations: AUD : alcohol use disorder (this term is used here to refer to patients with either "alcohol-dependence" according to the DSM-IV criteria or "alcohol use disorder" according to the DSM-5); HC: Healthy controls; KS: patients with Korsakoff's Syndrome; PSG : polysomnography: PSQI: Pittsburg sleep quality index [START_REF] Buysse | The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research[END_REF]; ISI : insomnia severity index [START_REF] Bastien | Validation of the Insomnia Severity Index as an outcome measure for insomnia research[END_REF] ; SIP questionnaire: short index of problems [START_REF] Feinn | Psychometric Properties of the Short Index of Problems as a Measure of Recent Alcohol-Related Problems[END_REF]; IDTS questionnaire: inventory of drug-taking situations [START_REF] Turner | Measurement of antecedents to drug and alcohol use: Psychometric properties of the Inventory of Drug-Taking Situations[END_REF] ; CT: computed tomography; GM: gray matter; WM: white matter; DTI: diffusion tensor imaging; REM: rapid eye movement; SWS: slow wave sleep;

FIGURES AND TABLES

NREM: non rapid eye movement; /: not available.

For age, duration of alcohol dependence and abstinence before inclusion, the mean was reported and the standard-deviation when this information was available.

PRACTICE POINTS

• Sleep disturbances are very frequent at all stages of alcohol use disorder (i.e. from active alcohol use to sustained abstinence) and can favor relapse.

• Complex bidirectional relationships seem to exist between sleep and alcohol use disorder: sleep disturbances could be the consequence of alcohol-related brain damage, but may also contribute to brain alterations and cognitive deficits.

• Sleep may contribute to the heterogeneity of brain alterations and cognitive deficits observed in patients with in alcohol use disorder.

• Long-lasting sleep difficulties may contribute to persistent functional and structural brain abnormalities in alcohol use disorder.

• Clinicians in Addiction departments should pay a particular attention to sleep disorders to optimize treatment of AUD patients.

CONFLICTS OF INTEREST:

The authors have no conflicts of interest to disclose.

Figure 1 :

 1 Figure 1: Objective and subjective sleep disturbances at each stage of AUD. This figure summarizes objective and subjective sleep disturbances in AUD patients during active alcohol use, acute withdrawal phase, early in abstinence (< 2 months of abstinence) and late in abstinence (> 2 months of abstinence). ↑ : increased compared to controls or baseline in the case of longitudinal studies ; ↓ : decreased compared to controls or baseline in the case of longitudinal studies. The doted arrows indicate inconsistent results (for more details, see section 2: Alcohol-induced sleep abnormalities).

Figure 2 :

 2 Figure 2: Contribution of sleep disturbances to alcohol-related brain alterations and

Table 1 : Descriptive characteristics and main findings of studies conducted on the relationships between sleep disturbances, brain abnormalities and cognitive impairments in abstinent AUD patients.

 1

Table 1 : Descriptive characteristics and main findings of studies conducted on the relationships between sleep disturbances, brain abnormalities and cognitive impairments in abstinent AUD patients.

 1

	Authors, (reference number)	Sample size	Mean age (years)	Duration of alcohol dependence	Abstinence before inclusion	Sleep measure	Neuropsychological assessment	Neuroimaging variables	Main results
	Benson et al., 1978 [140]	AUD: 20 No controls	46.9	13.9 years (alcohol misuse)	77.6 days	PSG	Working memory (Digit span task)	/	Significant positive correlation between lower percentage of REM sleep and digit span performance.
	Ishibashi et al., 1987 [157]	AUD: 9 No controls	43 ± 7.76	> 10 years	180 days	PSG	/	GM volumes (CT scan)	Significant association between lower percentage of SWS and cortical atrophy.
	Junghanns et al., 2009 [79]	AUD: 36 (24 early abstainers (EA) and 12 longer abstainers (LA)) No controls	EA: 40.8 ± 6.2 LA: 40.0 ± 9.0	EA: 116.3 ± 75.6 months LA: 160.7 ± 96.8 months	EA: 21.9 ± 7.6 days LA: 115.7 ± 43.8 days	PSG	Declarative memory (face-name association task) Procedural memory (Mirror-tracing task)	/	Significant association between alcohol-related NREM sleep alteration and decrease in declarative memory performance.
	Colrain et al., 2011 [158]	AUD: 40 HC: 40	AUD-M: 50.2 ± 7.5 AUD-W: 49 ± 9.6 HC-M: 51.1 ± 10.3 HC-W: 51.6 ± 10.1	AUD-M: 27.5 ± 8.8 years AUD-W: 22.7 ± 9.4 years	AUD-M: 135.9 ± 147 days AUD-W: 260.2 ± 209.6 days	PSG	/	GM volumes (MRI)	Lower regional GM volumes contributed to the changes in the amplitude of K-complexes.
	Chaudhary et al., 2015 [55]	AUD: 123 No controls	44 ± 10.3	/	At least 3 days	ISI	Psychosocial problems (SIP questionnaire)	/	Moderate to severe insomnia was associated with higher psychosocial problems.
	Liu et al., 2019 [165]	AUD: 15 HC: 15	AUD: 47.3 ± 5 HC: 47.3 ± 4.9	/	At least 2 days	PSQI	/	Resting state functional connectivity	Functional abnormalities within thalamocortical circuits were associated with drinking behavior and sleep impairments.
	Laniepce et al., 2019 [141]	KS: 17 AUD: 37 HC: 20	KS: 56.41 ± 4.79 AUD: 45.59 ± 9.21 HC: 42.50 ± 5.94	AUD: 8.65 ± 7.73 years KS: not available	AUD: 10.5 ± 3.99 days KS: > 10 years	PSQI	Executive functions (composite score) Episodic memory (composite score)	GM volumes (MRI) WM integrity (DTI)	In AUD and KS patients, the absence of sleep complaint reflects the presence of severe executive deficits and fronto thalamic damage.
	Kolla et al., 2020 [149]	AUD: 303 No controls	AUD: 42.22 ± 11.57	/	At least 5 days	PSQI	Self-report alcohol-related psychosocial problems (IDTS questionnaire)	/	Significant positive association between sleep disturbance and the propensity to drink when experiencing unpleasant emotions and conflict.

RESEARCH AGENDA

• Research needs to clarify the particular aspects of sleep quality, architecture and microstructure that are related to specific cognitive deficits in alcohol use disorder.

• Future studies are needed to specify the brain regions that are particularly vulnerable to poor sleep in alcohol use disorder.

• Longitudinal designs are required to better understand how sleep can modulate brain and cognitive recovery and to determine whether long-lasting poor sleep can explain, at least partly, the persistence of some cognitive deficits in patients with AUD.

• Studies combining sleep assessments, multimodal neuroimaging and cognitive evaluations are needed to improve our knowledge about sleep disturbances in alcohol use disorder, and adapt treatment strategies to reduce the risk of relapse.

Abbreviations

AUD: alcohol use disorder