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International audience; Aims: To specify the determinants of low-risk alcohol drinking and relapse at different timepoints after detoxification in patients with severe Alcohol Use Disorder (AUD).Methods: Fifty-four AUD patients and 36 healthy controls (HC) were evaluated early inabstinence (T1). They underwent clinical, neuropsychological and neuroimaging (structuralMRI and 18FDG-PET) investigations.AUD patients were subsequently classified as “low-risk drinkers” (LR) or “relapsers” (R)based on their alcohol drinking at 6 months (T2) and one year (T3) after discharge, using theirmedical record or self-reported drinking estimation at follow-up.Results: Based on the alcohol status at T2 and compared to HC, only R had alexithymia,lower gray matter volume in the midbrain and hypermetabolism in the cerebellum andhippocampi. Based on the alcohol status at T3 and compared to HC, only R had more severenicotinic dependence, lower episodic and working memory performance, lower gray mattervolume in the amygdala, ventromedial prefrontal cortex and anterior cingulate gyrus, andhypermetabolism in cerebellum, hippocampi and anterior cingulate gyrus. Moreover, R hadbilateral frontal hypometabolism, whereas LR only presented right frontal hypometabolism.Conclusion: Nicotine dependence, memory impairments, and structural brain abnormalitiesin regions involved in impulsivity and decision-making might contribute to a one-yearrelapse. Treatment outcome at one year may also be associated with an imbalance between ahypermetabolism of the limbic system and a hypometabolism of the frontal executive system.Finally, cerebellar hypermetabolism and alexithymia may be determinants of relapse at both 6months and one year.

International audience; Chronic and excessive alcohol consumption can result in alcohol use disorder (AUD) without neurological complications and in Korsakoff's syndrome (KS) when combined with thiamine deficiency. These two clinical forms are accompanied by widespread structural brain damage in both the fronto-cerebellar (FCC) and Papez circuits (PC) as well as in the parietal cortex, resulting in cognitive and motor deficits. BEARNI is a screening tool especially designed to detect neuropsychological impairments in AUD. However, the sensitivity of this tool to the structural brain damage of AUD and KS patients remains unknown. Eighteen KS patients, 47 AUD patients and 27 healthy controls (HC) underwent the BEARNI test and a 3 T-MRI examination. Multiple regression analyses conducted between GM density and performance on each BEARNI subtest revealed correlations with regions included in the FCC, PC, thalamus and posterior cortex (precuneus and calcarine regions). All these brain regions were altered in KS compared to HC, in agreement with the cognitive deficits observed in the corresponding BEARNI subtests. The comparison between KS and AUD regarding the GM density in the several nodes of the FCC and calcarine regions revealed that they were atrophied to the same extent, suggesting that BEARNI is sensitive to the severity of alcohol-related GM abnormalities. Within the PC, the density of the cingulate cortex and thalamus, which correlated with the memory and fluency subscores, was smaller in KS than in AUD, suggesting that BEARNI is sensitive to specific brain abnormalities occurring in KS.

Alcohol Use Disorder (AUD) results in sleep disturbances that may have deleterious impacts on cognition, especially on memory. However, little is known about the sleep architecture in patients with Korsakoff’s syndrome (KS). This study aims at characterizing sleep disturbances in KS compared to AUD without KS and at specifying the relationships with cognitive impairments. Twenty-nine AUD patients (22 without KS and 7 with KS) and 15 healthy controls underwent a neuropsychological assessment and a polysomnography. The severity of sleep-disordered breathing and sleep fragmentation was similar in AUD and KS patients compared to controls. Sleep architecture differed between both patient groups: the proportion of slow-wave sleep was reduced in AUD patients only, while a lower proportion of rapid-eye movement (REM) sleep was specifically observed in KS patients. The proportion of REM sleep correlated with the severity of episodic memory deficits when AUD and KS were examined together. These data provide evidence for both similarities and specificities regarding sleep alterations in AUD patients with and without KS. They also indicate that altered sleep architecture may contribute to the pathophysiology of alcohol-related memory disorders.

International audience; 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.

This work was supported by the French National Institute for Health and Medical Research (INSERM), the French National Agency for Research (ANR) Postdoc Return (Retour PostDoctorants, PDOC) program, the Regional council of Lower-Normandy, and the Mission Interministerielle de Lutte contre les Drogues Et les Conduites Addictives (MILDECA).; International audience; Background: The aim of the present study was to determine whether the Brief Evaluation of Alcohol‐Related Neuropsychological Impairments (BEARNI), a screening tool developed to identify neuropsychological deficits in Alcohol Use Disorder (AUD) patients, can also be used as a relevant tool for the early identification of AUD patients at risk of developing Korsakoff’s syndrome (KS).Methods: Eighteen KS patients, 47 AUD patients and 27 healthy controls underwent BEARNI (including five subtests targeting episodic memory, working memory, executive function, visuospatial abilities and ataxia) and a comprehensive neuropsychological examination.Results: Performance of AUD and KS patients on BEARNI subtests is in accordance with the results on the standardized neuropsychological assessment. On BEARNI, ataxia and working memory deficits observed in AUD were as severe as those exhibited by KS patients, whereas for visuospatial abilities, a graded effect of performance was found. On the opposite, the subtests involving long‐term memory abilities (episodic memory and fluency) were impaired in KS patients only. AUD patients with a score lower than 1.5 points (/6) on the episodic memory subtest of BEARNI could be considered at risk of developing KS and exhibited the lowest episodic memory performance on the neuropsychological battery.Conclusions: These findings suggest that BEARNI is a relevant tool to detect severe memory impairments, thus making early identification of AUD patients at high risk of developing KS possible.

In alcohol use disorder, drinking cessation is frequently associated with an alcohol withdrawal syndrome. Early in abstinence (within the first 2 months after drinking cessation), when patients do not exhibit physical signs of alcohol withdrawal syndrome anymore (such as nausea, tremor or anxiety), studies report various brain, sleep and cognitive alterations, highly heterogeneous from one patient to another. While the acute neurotoxicity of alcohol withdrawal syndrome is well-known, its contribution to structural brain alterations, sleep disturbances and neuropsychological deficits observed early in abstinence has never been investigated and is addressed in this study. We included 54 alcohol use disorder patients early in abstinence (from 4 to 21 days of sobriety) and 50 healthy controls. When acute physical signs of alcohol withdrawal syndrome were no longer present, patients performed a detailed neuropsychological assessment, a T1-weighted MRI and a polysomnography for a subgroup of patients. According to the severity of the clinical symptoms collected during the acute withdrawal period, patients were subsequently classified as mild alcohol withdrawal syndrome (mild-AWS) patients (Cushman score ≤ 4, no benzodiazepine prescription, N = 17) or moderate alcohol withdrawal syndrome (moderate-AWS) patients (Cushman score > 4, benzodiazepine prescription, N = 37). Patients with severe withdrawal complications (delirium tremens or seizures) were not included. Mild-AWS patients presented similar grey matter volume and sleep quality as healthy controls, but lower processing speed and episodic memory performance. Compared to healthy controls, moderate-AWS patients presented non-rapid eye movement sleep alterations, widespread grey matter shrinkage and lower performance for all the cognitive domains assessed (processing speed, short-term memory, executive functions and episodic memory). Moderate-AWS patients presented a lower percentage of slow-wave sleep, grey matter atrophy in fronto-insular and thalamus/hypothalamus regions, and lower short-term memory and executive performance than mild-AWS patients. Mediation analyses revealed both direct and indirect (via fronto-insular and thalamus/hypothalamus atrophy) relationships between poor sleep quality and cognitive performance. Alcohol withdrawal syndrome severity, which reflects neurotoxic hyperglutamatergic activity, should be considered as a critical factor for the development of non-rapid eye movement sleep alterations, fronto-insular atrophy and executive impairments in recently detoxified alcohol use disorder patients. The glutamatergic activity is involved in sleep-wake circuits and may thus contribute to molecular mechanisms underlying alcohol-related brain damage, resulting in cognitive deficits. Alcohol withdrawal syndrome severity and sleep quality deserve special attention for a better understanding and treatment of brain and cognitive alterations observed early in abstinence, and ultimately for more efficient relapse prevention strategies., Even in the absence of severe alcohol withdrawal syndrome, moderate alcohol withdrawal syndrome was associated with a lower percentage of slow-wave sleep, which related to cognitive deficits both directly and indirectly via grey matter shrinkage. Alcohol withdrawal syndrome severity seems to contribute to the pathophysiology of brain, sleep and cognitive damage in alcohol use disorder patients., Graphical Abstract Graphical Abstract

Well before the development of severe alcohol-related neurological complications such as Korsakoff’s syndrome (KS), patients with Alcohol Use Disorder (AUD) exhibit variable brain damage and cognitive deficits, as well as sleep disturbances. Although it is well established that sleep contributes to brain and cognitive functioning, its involvement in brain damage and cognitive deficits in AUD remains poorly understood. The objective of this thesis was to investigate subjective and objective sleep quality in AUD and KS patients, and its relationships with brain structure and function. Our results show that sleep complaint must be interpreted with regard to the severity of brain alterations and cognitive impairments in AUD and KS patients. Moreover, we showed a high prevalence of sleep apnea in these patients. REM sleep abnormalities are specifically observed in KS patients and related to the severity of memory deficits. Regarding AUD patients, we highlight the contribution of the severity of withdrawal syndrome in slow wave sleep decrease, and its effects on brain and cognitive functioning. Hence, similarities and differences of sleep architecture have been found in the two clinical forms (AUD and KS). These sleep modifications could depend on the severity of alcohol withdrawal and be involved in the pathophysiology of alcohol-related structural brain damage and cognitive impairment. These results encourage evaluating and managing both alcohol withdrawal and sleep modifications to improve patients’ prognosis at discharge from Addiction department.; En amont du développement de complications neurologiques sévères telles que le syndrome de Korsakoff (SK), les patients présentant un Trouble de l’Usage d’Alcool (TUAL) présentent des altérations cérébrales et cognitives de nature et de sévérité variables, ainsi que des troubles du sommeil. Bien qu’il soit clairement établi que le sommeil contribue au fonctionnement cérébral et cognitif, son implication comme facteur explicatif des atteintes cérébrales et cognitives dans le TUAL reste peu documentée. L’objectif de cette thèse était de préciser les modifications (subjectives et objectives) du sommeil chez les patients TUAL et SK, et leurs liens avec la structure cérébrale et le fonctionnement cognitif. Nos résultats montrent que la plainte de sommeil doit être interprétée au regard de la sévérité des atteintes cérébrales et cognitives chez les patients TUAL et SK. De plus, nous montrons qu’une proportion élevée de patients présentent des apnées du sommeil. Chez les patients SK, une atteinte spécifique du sommeil paradoxal est observée, associée à la sévérité des difficultés mnésiques. Enfin, chez les patients TUAL, nous montrons le rôle particulier de la sévérité du syndrome de sevrage dans l’atteinte du sommeil lent profond, et son impact sur le fonctionnement cérébral et cognitif. Ainsi, il semble exister des similarités et des différences dans l’architecture du sommeil de ces deux formes cliniques (TUAL et SK). Ces modifications de sommeil dépendraient de la sévérité du sevrage et seraient impliquées dans la physiopathologie des atteintes structurales et cognitives liées à l’alcool. Ces résultats soulignent la nécessité d’évaluer et de prendre charge à la fois le sevrage et les modifications du sommeil des patients TUAL afin d’améliorer le pronostic des patients à la sortie des services hospitaliers.

Substance use disorder develops from complex interactions between socio-environmental and neurobiological factors. A neurocognitive model of addiction, the triadic model, proposes that Alcohol Use Disorder (AUD) is the result of an imbalance between the reflective and the impulsive subcomponents along with a disruption of the regulatory subcomponent. Physical activity is considered as an emerging treatment for severe AUD (sAUD). This short review examines the efficacy and mechanisms of action of physical intervention as an adjunctive treatment in severe AUD (sAUD) within the theoretical framework of the triadic model. Physical activity is a feasible, safe, and less stigmatizing approach than classical treatments. It improves sAUD patients’ mental and physical comorbidities. The key finding of this short review is that physical activity could contribute to a rebalancing of the triadic model in sAUD patients by 1) improving neuroplasticity and cognitive functioning, 2) reducing impulsivity and urgency, and improving emotional regulation, and 3) reducing craving. This rebalancing could eventually reduce the risk of relapse. However, due to methodological issues, it remains difficult to observe an effect of physical activity on drinking outcomes. At best, a trend towards a reduction in alcohol consumption was noted. The mechanisms that could explain the benefits of physical activity in sAUD patients involve multiple physiological processes such as dopaminergic or glutamatergic transmission and signaling or neuroplasticity. Future randomized controlled trials should include neuropsychological and impulsivity assessments, in more controlled environments. Physical activity could contribute to a personalization of sAUD treatment using each subcomponent of the triadic model as a therapeutic target. Physical exercise could be an adjunctive treatment for sAUD patients, favoring the benefit of more usual treatments such as cognitive behavioral therapies. It could also be a stand-alone intervention in less severe patients.

Background Despite severe structural brain abnormalities within the frontocerebellar circuit (FCC), cerebellar metabolism studied with 18 F-2-fluoro-deoxy-glucose-positron emission tomography (FDG-PET) is relatively preserved in patients with alcohol use disorder (AUD). The compensatory role of the cerebellum has been explored mainly through fMRI examination of AUD patients with the preserved level of performance. The present study aims at examining cerebellar metabolism and its relationship with regional brain metabolism and neuropsychological functioning in AUD patients. Methods Thirty-two recently detoxified AUD patients and 23 controls underwent an FDG-PET examination at rest. Participants also performed a neuropsychological battery assessing executive functions, verbal memory, and ataxia. Results Compared to controls, AUD patients had higher glucose uptake in the cerebellar lobule VIII, in association with hypometabolism, notably in several nodes of the FCC. Cerebellar hypermetabolism correlated negatively with regional hypometabolism in the premotor and frontal cortices. This pattern of regional hypermetabolism and hypometabolism related to ataxia and working memory deficits. Conclusions These specific brain-behavior relationships do not fulfill the criteria for brain compensatory processes. Cerebellar hypermetabolism may rather reflect the involvement of different pathological mechanisms, leading to a maladaptive plasticity phenomenon within the FCC in AUD patients who are early in abstinence. Further studies are required to examine the contributions of structural and functional connectivity alterations in the cerebellar hypermetabolism and the changes in these pathological mechanisms with abstinence or relapse.

Alcohol is a psychoactive substance consumed worldwide and directly responsible or at least contributing to the development of diseases such as alcohol use disorder (AUD), cirrhosis, fetal alcohol syndrome, cancer, and cardiovascular diseases. The past decades of research have revealed brain structural and functional abnormalities associated with mild to moderate cognitive impairment in recently detoxified AUD patients. Such functional compromise can be detectable even before the development of more chronic and severe neurological complications such as Korsakoff’s syndrome (KS) and alcohol-related dementia (ARD). Excessive alcohol consumption results in impairment in attention, executive functions, memory, visuospatial and motor skills, as well as deficits in metamemory processes, emotion recognition, and theory of mind abilities. As a consequence, early in abstinence, some AUD patients may not be cognitively able to benefit from therapies and could be at risk to relapse because cognitive impairment hampers efficient decision-making, motivation to change, and learning skills, in addition to challenging emotional and interpersonal interactions. This chapter describes the alcohol-related cognitive impairment observed in recently detoxified AUD patients. It then discusses potential cognitive recovery or persistence of these deficits with prolonged abstinence and their clinical implications in terms of treatment and abstinence or relapse. The specificity of the AUD cognitive and motor profile is contrasted with alcohol-related neurological complications (i.e., KS and ARD) and other neurocognitive disorders (i.e., Alzheimer’s disease and frontotemporal dementia). Finally, structural and functional brain abnormalities as well as their relationship with neuropsychological impairments are presented.