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Background: Alzheimer’s disease (AD) and Korsakoff’s syndrome (KS) are two major neurocognitive disorders characterized by amnesia but AD is degenerative while KS is not. The objective is to compare regional volume deficits within the Papez circuit in AD and KS, considering AD progression. Methods: 18 KS patients, 40 AD patients (20 with Moderate AD (MAD) matched on global cognitive deficits with KS patients and 20 with Severe AD (SAD)), and 70 healthy controls underwent structural MRI. Volumes of the hippocampi, thalami, cingulate gyri, mammillary bodies (MB) and mammillothalamic tracts (MTT) were extracted. Results: For the cingulate gyri, and anterior thalamic nuclei, all patient groups were affected compared to controls but did not differ between each other. Smaller volumes were observed in all patient groups compared to controls in the mediodorsal thalamic nuclei and MB, but these regions were more severely damaged in KS than AD. MTT volumes were damaged in KS only. Hippocampi were affected in all patient groups but more severely in the SAD than in the KS and MAD. Conclusions: There are commonalities in the pattern of volume deficits in KS and AD within the Papez circuit with the anterior thalamic nuclei, cingulate cortex and hippocampus (in MAD only) being damaged to the same extent. The specificity of KS relies on the alteration of the MTT and the severity of the MB shrinkage. Further comparative studies including other imaging modalities and a neuropsychological assessment are required.

Sleep plays a crucial role in memory consolidation. Recent data in rodents and young adults revealed that fast spindle band power fluctuates at a 0.02-Hz infraslow scale during non-rapid eye movement (NREM) sleep. These fluctuations result from a periodic temporal clustering of spindles and may modulate sleep maintenance and memory consolidation. With age, sleep undergoes substantial changes but age-related changes in spindle clustering have never been investigated. Polysomnography data were collected in 147 older (mean age ± SD: 69.3 ± 4.1 years) and 32 young-middle aged (34.5 ± 10.9 years) adults. Sleep-dependent memory consolidation was assessed in a subsample of 57 older adults using a visuospatial memory task. We analyzed power fluctuations in fast spindle frequency band, detected fast spindles, and quantified their clustering during the night separating encoding and retrieval. Fast spindle band power fluctuated at a 0.02-Hz infraslow scale in young-middle aged and older adults. However, the proportion of clustered fast spindles decreased non-linearly with age (p Clinical Trial Information: Name: Study in Cognitively Intact Seniors Aiming to Assess the Effects of Meditation Training (Age-Well). URL: https://clinicaltrials.gov/ct2/show/NCT02977819?term=Age-Well&draw=2&rank=1. See STROBE_statement_AGEWELL.doc in supplementary material. Registration: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

Introduction: The COVID-19 outbreak and the related lockdown measures have raised concerns regarding mental health, including alcohol misuse. Preliminary studies investigated alcohol consumption at the early stages of lockdown, but no longitudinal data regarding its evolution during and after the first lockdown are currently available. Methods: We investigated changes in alcohol consumption among a convenience sample of 1,693 French-speaking Belgian adults using a 3-stage longitudinal online survey. All participants reported their consumption at different stages of lockdown: before lockdown onset (retrospectively, T0), at 2 different times during lockdown (T1 and T2), and after lockdown offset (T3). We also measured socio-demographic variables and the harmfulness of drinking patterns before lockdown. Results: A mixed model with negative binomial distribution indicated that participants decreased their alcohol consumption after lockdown onset and returned to their initial alcohol consumption after lockdown offset. Younger individuals (18–30 years old) were more likely to decrease their consumption during the lockdown period (T1 and T2) than the periods preceding or following lockdown (T0 and T3), especially if they presented hazardous or problematic drinking patterns before lockdown. We only observed a rebound effect after lockdown offset among young moderate drinkers. All participants kept stable their alcohol consumption during lockdown (T1 and T2). Conclusions: Lockdown onset and offset constitute key periods for alcohol consumption changes during the COVID-19 crisis, particularly in youth and in individuals with hazardous or problematic drinking patterns.

ObjectivesTo compare regional volume deficits within the Papez circuit in Alzheimer’s disease (AD) and Korsakoff’s syndrome (KS), taking into account the neurodegenerative nature of AD.Methods18 KS patients, 40 AD patients (20 with Moderate AD (MAD) matched on cognitive deterioration with KS patients and 20 with Severe AD (SAD)), and 70 healthy controls underwent structural MRI examination. Volumes of the hippocampi, thalami, cingulate gyri, mammillary bodies (MB) and mammillothalamic tracts (MTT) were extracted.ResultsFor the anterior and posterior cingulate gyri, and anterior thalamic nuclei, all patient groups were significantly affected compared to controls but did not differ between each other. Lower volumes were observed in all patient groups compared to controls in the entire thalamus, mediodorsal thalamic nuclei and MB, but these regions were more severely damaged in KS compared to AD. MTT volumes were significantly damaged in KS only. Hippocampi were affected in all patient groups but more severely in the SAD than in the KS and MAD.InterpretationThe specificity of KS compared to AD relies on the severity of the MB and mediodorsal nuclei shrinkage, as well as the atrophy of the MTT. Several nodes of the Papez circuit were damaged to the same extent in AD and KS: the anterior thalamic nuclei, the cingulate cortex and the hippocampus (in MAD only). Our results encourage considering common mechanisms in the pathophysiology of amnesia regardless of etiology and question the relevance of the classical distinction between hippocampal and diencephalic amnesia.

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.

TrimethylamineTMAO and IS were quantified in thirty AUD inpatients and fifteen healthy controls (HC). The severities of AUD and alcohol withdrawal syndrome (AWS), and general cognitive abilities were assessed in AUD patients.TMAO concentrations did not differ between HC and AUD patients. Several biomarkers assessing nutritional status and liver function were significantly different in AUD patients with the lowest TMAO concentrations compared to other AUD patients. IS concentration was significantly lower in AUD patients and a significant positive predictor of serum prealbumin variation during the acute phase of alcohol withdrawal. No relationship was observed between the concentrations of these metabolites and the severities of alcohol dependence, AWS, or cognitive deficits.Our data suggest that AUD patients with low concentrations of TMAO or IS should probably benefit from a personalized refeeding program during the acute phase of alcohol withdrawal.

International audience; In healthy populations, visual abilities are characterized by a faster and more efficient processing of global features in a stimulus compared to local ones. This phenomenon is known as the global precedence effect (GPE), which is demonstrated by (1) a global advantage, resulting in faster response times for global features than local features and (2) interference from global distractors during the identification of local targets, but not vice versa. This GPE is essential for adapting visual processing in everyday life (e.g., extracting useful information from complex scenes). We investigated how the GPE is affected in patients with Korsakoff's syndrome (KS) compared to patients with severe alcohol use disorder (sAUD). Three groups (including healthy controls, patients with KS and patients with sAUD) completed a global/local visual task in which predefined targets appeared at the global or local level during either congruent or incongruent (i.e., interference) situations. The results showed that healthy controls (N = 41) presented a classical GPE, while patients with sAUD (N = 16) presented neither a global advantage nor global interference effects. Patients with KS (N = 7) presented no global advantage and an inversion of the interference effect, characterized by strong interference from local information during global processing. The absence of the GPE in sAUD and the interference from local information in KS have implications in daily-life situations, providing preliminary data for a better understanding of how these patients perceive their visual world.

Sleep plays a crucial role in memory consolidation. Recent data in rodents and young adults revealed that fast spindle band power fluctuates at a 0.02-Hz infraslow scale during non-rapid eye movement (NREM) sleep. These fluctuations result from a periodic temporal clustering of spindles and may modulate sleep maintenance and memory consolidation. With age, sleep undergoes substantial changes but age-related changes in spindle clustering have never been investigated. Polysomnography data were collected in 147 older (mean age ± SD: 69.3 ± 4.1 years) and 32 young-middle aged (34.5 ± 10.9 years) adults. Sleep-dependent memory consolidation was assessed in a subsample of 57 older adults using a visuospatial memory task. We analyzed power fluctuations in fast spindle frequency band, detected fast spindles and quantified their clustering during the night separating encoding and retrieval. Fast spindle band power fluctuated at a 0.02-Hz infraslow scale in young-middle aged and older adults. However, the proportion of clustered fast spindles decreased non-linearly with age (p0.001). This effect was not mediated by NREM sleep fragmentation. The clustering level of fast spindles modulated their characteristics (p0.001). Finally, the mean size of spindle clusters was positively associated with memory consolidation (p = 0.036) and negatively with NREM sleep micro-arousals density (p = 0.033). These results suggest that clusters of fast spindles may constitute stable sleep periods promoting off-line processes such as memory consolidation. We emphasize the relevance of considering spindle dynamics, obviously impaired during ageing, to understand the impact of age-related sleep changes on memory.

Background: Alzheimer’s disease (AD) and Korsakoff’s syndrome (KS) are two major neurocognitive disorders characterized by amnesia but AD is degenerative while KS is not. The objective is to compare regional volume deficits within the Papez circuit in AD and KS, considering AD progression. Methods: 18 KS patients, 40 AD patients (20 with Moderate AD (MAD) matched on global cognitive deficits with KS patients and 20 with Severe AD (SAD)), and 70 healthy controls underwent structural MRI. Volumes of the hippocampi, thalami, cingulate gyri, mammillary bodies (MB) and mammillothalamic tracts (MTT) were extracted. Results: For the cingulate gyri, and anterior thalamic nuclei, all patient groups were affected compared to controls but did not differ between each other. Smaller volumes were observed in all patient groups compared to controls in the mediodorsal thalamic nuclei and MB, but these regions were more severely damaged in KS than AD. MTT volumes were damaged in KS only. Hippocampi were affected in all patient groups but more severely in the SAD than in the KS and MAD. Conclusions: There are commonalities in the pattern of volume deficits in KS and AD within the Papez circuit with the anterior thalamic nuclei, cingulate cortex and hippocampus (in MAD only) being damaged to the same extent. The specificity of KS relies on the alteration of the MTT and the severity of the MB shrinkage. Further comparative studies including other imaging modalities and a neuropsychological assessment are required.

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.

Perfectionistic individuals present exaggerated performance standards, generating a constant search for flawlessness and a high tendency to self-criticize. Dominant models distinguish three dimensions of perfectionism: namely, self-oriented, socially prescribed and other-oriented. Perfectionism constitutes a vulnerability factor for psychopathological disorders, but its role in severe alcohol use disorder (SAUD) remains unexplored.Sixty-five recently detoxified patients with SAUD and 65 matched controls completed a perfectionism questionnaire (the Hewitt Multidimensional Perfectionism Scale), together with measures of psychopathology.SAUD was associated with greater self-oriented and socially prescribed perfectionism, with no group differences on other-oriented perfectionism. This differential pattern persisted when controlling for depression and anxiety levels, and there was no correlation with alcohol consumption.This specific perfectionistic profile is consistent with those of previous studies showing lower self-evaluation (e.g., higher self-blame and reduced self-esteem) and impaired social cognition (e.g., unrealistic social standards and greater social isolation) in SAUD. In view of its potential role in the development and maintenance of SAUD, perfectionism may constitute a valuable treatment target in patients with this disorder.

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.

ObjectiveTo investigate cognitive and brain changes in patients with Korsakoff syndrome (KS) over months and up to 10 years after the diagnosis.MethodsTwo groups of 8 patients with KS underwent neuropsychological, motor, and neuroimaging investigations, including structural MRI and 18F-fluorodeoxyglucose-PET. The KSC group, recruited at Caen University Hospital, was examined early after the KS diagnosis (KSC-T1) and 1 year later (KSC-T2). The KSR group, recruited at nursing home at Roubaix, was evaluated 10 years after the diagnosis. Longitudinal comparisons in KSC explored short-term changes, while cross-sectional comparisons between KSC-T1 and KSR informed about long-term changes.ResultsNo cognitive, motor, or brain deterioration occurred over time in patients with KS. There was no clear improvement either, with only modest recovery in the frontocerebellar circuit. Compared to the norms, KSC-T1 had severe episodic memory impairments, ataxia, and some executive dysfunctions. They also presented widespread atrophy and hypometabolism as well as cerebellar hypermetabolism compared to 44 healthy matched controls. Episodic memory remained significantly impaired in KSC-T2 and KSR. Contrary to KSC at T1 and T2, KSR had preserved inhibition abilities. Atrophy was similar but less extended in KSC-T2 and even more limited in KSR. At all times, the thalamus, hypothalamus, and fornix remained severely atrophied. Hypometabolism was still widespread in KSC-T2 and KSR, notably affecting the diencephalon. Cerebellar metabolism decreased over time and normalized in KSR, whereas motor dysfunction persisted.ConclusionIn KS, structural and metabolic alterations of the Papez circuit persisted over time, in accordance with the irreversible nature of amnesia. There was neither significant recovery as observed in patients with alcohol use disorder nor progressive decline as in neurodegenerative diseases.

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

International audience; Ageing is characterized by a progressive decline of sleep quality. Sleep difficulties are increasingly recognized as a risk factor for Alzheimer's disease (AD), and have been associated with cognitive decline. However, the brain substrates underlying this association remain unclear. In this review, our objective was to provide a comprehensive overview of the relationships between sleep changes and brain structural, functional and molecular integrity, including amyloid and tau pathologies in cognitively unimpaired older adults. We especially discuss the topography and causality of these associations, as well as the potential underlying mechanisms. Taken together, current findings converge to a link between several sleep parameters, amyloid and tau levels in the CSF, and neurodegeneration in diffuse frontal, temporal and parietal areas. However, the existing literature remains heterogeneous, and the specific sleep changes associated with early AD pathological changes, in terms of topography and neuroimaging modality, is not clearly established yet. Notably, if slow wave sleep disruption seems to be related to frontal amyloid deposition, the brain correlates of sleep-disordered breathing and REM sleep disruption remains unclear. Moreover, sleep parameters associated with tau- and FDG-PET imaging are largely unexplored. Lastly, whether sleep disruption is a cause or a consequence of brain alterations remains an open question.

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.

Points cles Le trouble de l’usage d’alcool est une maladie du cerveau resultant d’un desequilibre entre trois systemes cerebraux et cognitifs. Un premier systeme, dit reflexif, sous-tendu par le cortex frontal et correspondant aux fonctions executives et jouerait un role de controle des consommations d’alcool. Un second systeme, dit impulsif, sous-tendu par le complexe amygdalo-striatal, favorisait les comportements automatiques et impulsifs de consommation d’alcool. Un systeme regulateur, sous-tendu par l’insula et implique dans l’integration des perceptions proprioceptives dans des contextes de privation ou de stress, viendrait aggraver le desequilibre entre les deux premiers systemes. Ce modele offre une nouvelle grille de lecture du trouble de l’usage d’alcool et de nouvelles perspectives de cibles therapeutiques qui pourraient s’inscrire dans des programmes de soins integres et personnalises.

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.

International audience; The thalamus, a relay organ consisting of several nuclei, is shared between the frontocerebellar circuit and the Papez circuit, both particularly affected in alcohol use disorder. Shrinkage of the thalamus is known to be more severe in alcoholics with Korsakoff's syndrome than in those without neurological complications (uncomplicated alcoholics). While thalamic atrophy could thus be a key factor explaining amnesia in Korsakoff's syndrome, the loci and nature of alterations within the thalamic nuclei in uncomplicated alcoholics and alcoholics with Korsakoff's syndrome remains unclear. Indeed, the literature from animal and human models is disparate regarding whether the anterior thalamic nuclei, or the mediodorsal nuclei are particularly affected and would be responsible for amnesia. Sixty-two participants (20 healthy controls, 26 uncomplicated alcoholics and 16 patients with Korsakoff's syndrome) underwent a diffusion tensor imaging sequence and T1-weighted MRI. State-of-the-art probabilistic tractography was used to segment the thalamus according to its connections to the prefrontal cortex and cerebellar Cruses I and II for the frontocerebellar circuit's executive loop, the precentral gyrus and cerebellar lobes IV-VI for the frontocerebellar circuit's motor loop, and hippocampus for the Papez circuit. The connectivity and volumes of these parcellations were calculated. Tractography showed that the hippocampus was principally connected to the anterior thalamic nuclei while the prefrontal cortex was principally connected to the mediodorsal nuclei. The fibre pathways connecting these brain regions and their respective thalamic nuclei have also been validated. ANCOVA, with age and gender as covariates, on connectivity measures showed abnormalities in both patient groups for thalamic parcellations connected to the hippocampus only [F(2,57) = 12.1; P < 0.0001; η2 = 0.2964; with graded effects of the number of connections from controls to uncomplicated alcoholics to Korsakoff's syndrome]. Atrophy, on the other hand, was observed for the prefrontal parcellation in both patient groups and to the same extent compared to controls [F(2,56) = 18.7; P < 0.0001; η2 = 0.40]. For the hippocampus parcellation, atrophy was found in the Korsakoff's syndrome group only [F(2,56) = 5.5; P = 0.006; η2 = 0.170, corrected for multiple comparisons using Bonferroni, P < 0.01]. Post hoc Tukey's test for unequal sample sizes, healthy controls > patients with Korsakoff's syndrome (P = 0.0036). Two different mechanisms seem to affect the thalamus. In the frontocerebellar circuit, atrophy of the mediodorsal nuclei may lead to the alterations, whereas in the Papez circuit, disconnection between the anterior nuclei and hippocampus may be the leading factor. Shrinkage of the anterior nuclei could be specific to patients with Korsakoff's syndrome, hence a potential neuroimaging marker of its pathophysiology, or more generally of thalamic amnesia for which Korsakoff's syndrome has historically been used as a model.

Alcohol induced neurocognitive disorder: screening strategies and tools. Chronic and excessive alcohol consumption results in cognitive disorders partially reversible with abstinence. These heterogeneous cognitive impairments affect executive functions, episodic memory and social cognition. They may interfere with the motivational process to abandon excessive drinking behavior, impair patients' ability to benefit from treatment and increase the risk of relapse. Alcohol-related neuropsychological deficits should thus be evaluated and considered for personalized alcohol treatment. Several screening tools available in clinical settings enable clinicians to detect patients with cognitive impairments and to offer them appropriate and adjusted treatment.Repérage des troubles cognitifs liés à l’alcool. La consommation chronique et excessive d’alcool est fréquemment associée à des troubles cognitifs, en partie réversibles à l’arrêt de l’alcool. Variables d’un individu à l’autre, ils touchent principalement les fonctions exécutives et motrices, la mémoire épisodique, ainsi que la cognition sociale. Ces troubles peuvent freiner le processus motivationnel, amoindrir les capacités des patients à bénéficier des prises en charge et augmenter le risque de rechute. Plusieurs outils de dépistage rapide sont disponibles en pratique clinique. Ils permettent d’orienter les patients ayant une altération cognitive vers des prises en charge spécialisées pour la réalisation de bilans complémentaires. Le profil neuropsychologique des patients peut aussi éclairer les difficultés de prise en charge et permettre de personnaliser les soins addictologiques.

International audience; Prospective memory (PM) refers to our ability to perform actions at the appropriate 15 moment, either when a predetermined event occurs (event-based, EB) or after a predetermined 16 amount of time (time-based, TB). Sleep favors the consolidation of both EB and TB intentions, but 17 whether this benefit is preserved during ageing is still subject to debate. PM was assessed in 28 18 young and 27 older healthy volunteers using a virtual environment. Participants had to learn and 19 execute intentions after intervals filled with either daytime wakefulness or nighttime sleep. 20 Intentions consisted of four TB, four EB with a strong link between the cue triggering retrieval and 21 the action to be performed (EB-link) and four with no link (EB-nolink). PM was not affected by age, 22 whatever the type of intention and the nature of the retention interval. While sleep reinforced all 23 types of intentions in young participants, this benefit was only observed for TB and EB-link 24 intentions in older adults. Sleep also reinforced the intrinsic PM components in both groups. Thus, 25 when assessed using complex realistic situations, PM is not impaired in ageing. Results are 26 discussed in the light of memory schema theory and the possible impact of cognitive reserve on 27 sleep and memory. 28 29

Alcohol-related cognitive impairments are largely underestimated in clinical practice, even though they could limit the benefit of alcohol treatment and hamper the patient's ability to remain abstinent or to respect his/her therapeutic contract. These neuropsychological deficits can impact the management of patients well before the development of the well-known Korsakoff's syndrome. Indeed, even in the absence of ostensible neurological complications, excessive and chronic alcohol consumption results in damage of brain structure and function. The frontocerebellar circuit and the circuit of Papez, respectively involved in motor and executive abilities and episodic memory, are mainly affected. Those brain dysfunctions are associated with neuropsychological deficits, including deficits of executive functions, episodic memory, social cognition, as well as visuospatial and motor abilities. Such cognitive disorders can interfere with the motivation process to abandon maladjusted drinking behavior in favor of a healthier lifestyle (such as abstinence or controlled alcohol consumption). They can also limit the patient's capacity to fully benefit from treatment (notably psychoeducation and cognitive-behavioural treatments) currently widely proposed in French Addiction departments. In addition, they may contribute to relapse which is multi-determinated. A neuropsychological assessment appears therefore crucial to take relevant clinical decisions. However, very few addiction departments have the human and financial resources to conduct an extensive neuropsychological examination of all patients with alcohol dependence. Some brief screening tools can be used, notably the MOntreal Cognitive Assessment and the Brief Evaluation of Alcohol-Related Neuropsychological Impairments, which has been especially designed to assess cognitive and motor deficits in alcoholism. These tools can be used by non-psychologist clinicians to detect alcohol-related cognitive deficits, which require an extensive cognitive examination conducted by a neuropsychologist. The presence of cognitive dysfunctions in patients early in abstinence should encourage clinicians to adjust the modalities of the treatment. The fact to favor recovery of cognitive functions and brain volumes with abstinence or drastic reduction of alcohol consumption could be a first way to make it possible for patients to be cognitively able to benefit from treatment. Further studies are required to determine whether specifically designed cognitive remediation could boost (accelerate or increase) the recovery of brain functioning. Additionally, a potential effect of thiamine to limit alcohol-related cognitive deficits before the development of neurological complications remains to be determined. In this review, we presented the pattern of structural brain damage and the associated cognitive and motor impairments in alcohol-dependent patients. We then emphasized the harmful effects of neuropsychological deficits in the management of these patients. We also pointed how relevant it is to screen patients with neuropsychological impairments and we focused on the presentation of two brief screening tools for cognitive impairments, especially designed for alcohol-related deficits or not. Finally, we reported how these neuropsychological impairments could be taken into consideration the treatment of alcohol addiction by adjusting its timing and modalities.

Alcohol use disorder is a brain disease that can be modeled by an imbalance between three cerebral and cognitive systems. The reflective system, underpinned by the frontal cortex and corresponding to the executive functions, would be involved in the control of alcohol consumption. The impulsive system, underpinned by the amygdala-striatal complex, would favor automatic and impulsive drinking behaviors. A regulatory system, driven by insula and involved in the integration of proprioceptive perceptions in situations of deprivation or stress, would aggravate the imbalance between the two first systems. This model provides a new framework for understanding alcohol use disorder and new perspectives on therapeutic targets that could be included into integrated and customized treatments.

Objectif Le trouble de l’usage d’alcool (TUAL) est associe a des atteintes cerebrales et cognitives heterogenes, ainsi que des troubles du sommeil frequents. Le sommeil contribue a l’integrite des structures cerebrales et au bon fonctionnement cognitif. Nous cherchons donc a mieux comprendre l’impact des troubles du sommeil sur les anomalies structurales et cognitives retrouvees chez les patients TUAL. Methodes Huit patients presentant un TUAL severe et recemment abstinents (uniquement des hommes, 48,87 ± 7,5 ans) ont beneficie d’une IRM structurale ponderee en T1, d’une evaluation neuropsychologique et d’une polysomnographie. L’efficacite de sommeil a ete correlee au volume de substance grise cerebrale (SPM12) et aux performances cognitives (correlations de Spearman). Resultats L’efficacite de sommeil (86,9 ± 6,7 %) est negativement correlee aux volumes de substance grise dans le cervelet droit (Crus I et II) et la region mediodorsale du thalamus gauche, ainsi qu’aux performances de memoire de travail. Ces resultats restent significatifs lorsque l’âge, le niveau d’education, le score a l’Alcohol Use Disorders Identification Test, ou l’index d’apnees-hypopnees sont entrees en covariable. Conclusion Ces resultats preliminaires suggerent qu’un sommeil peu efficace pourrait contribuer aux alterations de certaines regions cerebrales notamment la boucle executive du circuit fronto-cerebelleux, se manifestant par la presence de deficits de memoire de travail chez les patients TUAL. Identifier et traiter les troubles de sommeil pourrait donc etre un element important afin d’optimiser la recuperation cognitive et la prise en charge des patients TUAL.

Les troubles du sommeil et l’alcoolo-dépendance (AD) sont deux comorbidités fréquemment associées dans les pathologies psychiatriques, telles que l’anxiété, la dépression, les troubles bipolaires ou la schizophrénie [1]. Depuis plusieurs années, les études conduites dans l’AD ont permis de mieux préciser les atteintes cognitives et cérébrales de ces patients [2]. Par ailleurs, certains résultats ont également souligné chez les AD la présence d’altérations du sommeil (36 à 72 % selon les études) qui seraient un facteur de risque de rechute [3]. En pratique clinique, l’évaluation du sommeil est principalement réalisée à l’aide de questionnaires, du fait de leur rapidité de passation et leur facilité d’analyse. L’objectif de cette étude est d’explorer les liens entre la plainte du sommeil évaluée à l’aide d’un autoquestionnaire nommé le « Pittsburg Sleep Quality Index » (PSQI) [4], les troubles cognitifs et les altérations cérébrales structurales des patients AD. Trente-neuf patients AD et 16 sujets sains recrutés au sein du protocole ALCOBRAIN ont été inclus dans la présente étude. Nos données indiquent que plus de 76 % des patients AD abstinents évoquent une plainte de sommeil. Les patients qui ne rapportent pas de plainte de sommeil présentent les troubles exécutifs les plus sévères. Par ailleurs, ces patients présenteraient également des altérations cérébrales plus importantes que ceux présentant une plainte de sommeil, notamment au sein de régions impliquées dans les capacités de métacognition. Ces résultats suggèrent qu’une forme infraclinique d’anosognosie pourrait être présente chez certains patients AD, entraînant une conscience partielle de leurs troubles du sommeil. En pratique clinique, il semble donc nécessaire de rester vigilant vis-à-vis de l’évaluation subjective du sommeil par le biais de questionnaires. Des études complémentaires sont nécessaires afin de préciser les liens entre sommeil, cognition et cerveau, notamment à l’aide de mesures objectives de la qualité du sommeil.

Objectif Plusieurs etudes suggerent une alteration de la consolidation des souvenirs au cours du sommeil chez le sujet âge, mais ceci reste controverse. Cette etude vise a mieux comprendre les liens entre les performances mnesiques, les modifications cerebrales structurales et la qualite du sommeil au cours du vieillissement. Methodes Seize sujets âges sains (65 ± 5,3 ans) ont realise une IRM structurale, une tâche de reconnaissance d’images 3 jours et 3 mois apres l’apprentissage, et une polysomnographie durant la nuit post-apprentissage. Des analyses de correlations ont ete menees entre les indices mnesiques obtenus a 3 jours et 3 mois (exactitude de la reconnaissance [d′] et nombre de fausses alarmes [FA]), l’epaisseur corticale et les parametres de sommeil. Seules les correlations dans le sens attendu sont rapportees. Resultats A 3 jours, les performances mnesiques ne sont pas correlees aux parametres de sommeil. A 3 mois, le nombre de FA est negativement correle a la quantite de sommeil lent profond (p = 0,009 ; r = −0,63) et le d′ positivement correle au pourcentage de stade 2 (p = 0,037 ; r = 0,52). Sur le plan neuro-anatomique, les 2 delais sont positivement correles a l’epaisseur corticale de la region pericalcarine (p Conclusion Cette etude montre qu’au cours du vieillissement, les modifications du sommeil sont correlees au declin des performances mnesiques, mais seulement apres un delai de 3 mois. A ce meme delai, les deficits mnesiques seraient sous-tendus par l’atteinte de la region para-hippocampique.