Insular volumetry in severe alcohol use disorder and Korsakoff's syndrome through an anatomical parcellation: Let us go back to basics.

Functional neuroimaging has demonstrated the key role played by the insula in severe alcohol use disorder (sAUD), notably through its involvement in craving and body signals processing. However, the anatomical counterpart of these functional modifications in sAUD patients with and without neurological complications remains largely unexplored, especially using state-of-the-art parcellation tools. We thus compared the grey matter volume of insular subregions (form anterior to posterior: anterior inferior cortex, anterior short gyrus, middle short gyrus, posterior short gyrus, anterior long gyrus, posterior long gyrus) in 50 recently detoxified patients with sAUD, 19 patients with Korsakoff's syndrome (KS) and 36 healthy controls (HC). We used a mixed linear model analysis to explore group differences in the six subregions grey matter volume and lateralization differences. Insular macrostructure was globally affected to the same extent in sAUD with and without KS, indicating that these brain abnormalities may be related to alcohol consumption per se, rather than to the presence of alcohol-related neurological complications. Insular atrophy showed a right-sided lateralization effect and was especially marked in the posterior insula, a region associated with visceral information processing and the embodiment effect of a substance, from which craving arises. Anatomical damages might thus underlie the previously reported altered insular activations and their behavioural counterparts.

[Women's vulnerability to alcohol and its impact on health]. / Vulnérabilité des femmes face à l'alcool et impacts sur la santé.

At the same level of consumption as men, specific vulnerabilities often expose women to the more rapid onset of more serious illnesses (cardiovascular and liver diseases, cancers, brain and cognitive damage, sleep disorders, risk of accidents, etc.). This worrying fact is still little known by the general population. Special prevention measures are needed, such as dedicated campaigns for women, specific guidelines for lower-risk drinking, systematic early detection of risky drinking among women, and brief intervention in the event of problem drinking.

Determinants of health-related quality of life in recently detoxified patients with severe alcohol use disorder.

BACKGROUND: Health-related quality of life (HRQoL) is an important clinical outcome in Alcohol Use Disorder (AUD) and is considered as a relevant indicator of treatment success. While a better understanding of the factors affecting HRQoL would enable to adjust patients' care to favour treatment outcome, the determinants of HRQoL in AUD remain unclear. This study aims at describing HRQoL in AUD patients and at identifying its best predictors. METHODS: 53 recently detoxified patients with severe AUD (sAUD) underwent a cognitive assessment and filled in a HRQoL questionnaire dedicated to AUD patients (Alcohol Quality of Life Scale; AQoLS), as well as questionnaires concerning socio-demographics, alcohol history, sleep quality, depression, anxiety and impulsivity. 38 healthy controls (HC) underwent the same assessment (except AQoLS) in order to identify the altered cognitive and clinical variables that could potentially be determinants of HRQoL in sAUD. RESULTS: sAUD patients reported that alcohol affects their HRQoL mainly in the "negative emotions", "control", "relationships", and "sleep" domains. Compared to HC, they were impaired on episodic memory, working memory, executive functions, and processing speed tasks. They also reported lower sleep quality, higher depression, anxiety and impulsivity. No association was found between AQoLS total score and socio-demographics, cognitive performance, or sleep quality in patients. We found a significant correlation between HRQoL and depression/anxiety as well as impulsivity. Anxiety and impulsivity were indeed the only significant predictors of HRQoL, explaining 47.7% of the variance. CONCLUSION: Anxiety and impulsivity are crucial determinants of HRQoL in recently detoxified sAUD patients. Since anxiety and impulsivity are frequent issues in addiction and especially in AUD, they should be particularly considered by clinicians to favour treatment outcomes.

Prognostic factors for low-risk drinking and relapse in alcohol use disorder: A multimodal analysis.

This study aims to specify the determinants of low-risk alcohol drinking and relapse at different time points after detoxification in patients with severe alcohol use disorder (AUD). Fifty-four patients with AUD and 36 healthy controls (HC) were evaluated early in abstinence (T1). They underwent clinical, neuropsychological and neuroimaging (structural MRI and 18 FDG-PET) investigations. Patients with AUD were subsequently classified as "low-risk drinkers" (LR) or "relapsers" (R) based on their alcohol drinking at 6 months (T2) and 1 year (T3) after discharge, using their medical record or self-reported drinking estimation at follow-up. Based on the alcohol status at T2 and compared with HC, only R had alexithymia, lower grey matter volume in the midbrain and hypermetabolism in the cerebellum and hippocampi. Based on the alcohol status at T3 and compared with HC, only R had more severe nicotinic dependence, lower episodic and working memory performance, lower grey matter volume in the amygdala, ventromedial prefrontal cortex and anterior cingulate gyrus and hypermetabolism in cerebellum, hippocampi and anterior cingulate gyrus. Moreover, R had bilateral frontal hypometabolism, whereas LR only presented right frontal hypometabolism. Nicotine dependence, memory impairments and structural brain abnormalities in regions involved in impulsivity and decision-making might contribute to a 1-year relapse. Treatment outcome at 1 year may also be associated with an imbalance between a hypermetabolism of the limbic system and a hypometabolism of the frontal executive system. Finally, cerebellar hypermetabolism and alexithymia may be determinants of relapse at both 6 months and 1 year.

Consommation d'alcool à risque : les séniors, grands oubliés des politiques de prévention.

With the aging of the population, it is necessary to implement prevention policies aimed at maintaining the elderly in good health and promoting their autonomy. Alcohol consumption is an avoidable risk factor in deteriorating health and loss of autonomy that can be addressed through targeted public health policies. We must consider both the long-term effects, by informing young people of the risks to their future health, and the deleterious short-term effects (accidents, falls) for older subjects. Even if there are recommendations for alcohol consumption issued by Santé Publique France, they are aimed at the general population and do not take into account the specificities of the elderly, whose vulnerability will depend both on current consumption and on the history of alcohol use during their lives. Several countries have issued recommendations specifically for this population, but the definitions of alcohol units vary from one country to another, making it very difficult to apply these recommendations in France. A public health policy specifically addressing the alcohol consumption of seniors in France is therefore absolutely crucial.

Early Identification of Alcohol Use Disorder Patients at Risk of Developing Korsakoff's Syndrome.

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 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 testing (including 5 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 was consistent 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. In contrast, 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 (out of 6) on the episodic memory subtest of BEARNI exhibited the lowest episodic memory performance on the neuropsychological battery and could be considered at risk of developing KS. CONCLUSIONS: These findings suggest that BEARNI is a useful tool for detecting severe memory impairments, suggesting that it could be used for the early identification of AUD patients at high risk of developing KS.

Dissociating thalamic alterations in alcohol use disorder defines specificity of Korsakoff's syndrome.

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.

Cerebellar Hypermetabolism in Alcohol Use Disorder: Compensatory Mechanism or Maladaptive Plasticity?

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.

[Pharmaceutical cognitive doping in students: a chimeric way to get-a-head?] / Dopage cognitif chez les étudiants : un moyen chim(ér)ique de s'en mettre plein la tête ?

For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit / risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta-blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices.

Pharmaceutical cognitive doping in students: A chimeric way to get-a-head?

For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit/risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta-blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices.

Are we just talking in circles? Impact of psychoeducation on disease knowledge and relapse in severe alcohol use disorder.

BACKGROUND: Psychoeducation constitutes a routine therapeutic practice in most treatment settings for severe alcohol use disorder (sAUD). This technique is considered an efficient way to help patients to learn more about their disease and achieve therapeutic objectives. However, this approach capitalizes on three untested assumptions: namely, that (1) patients with sAUD possess insufficient knowledge about sAUD at treatment entry; (2) patients with sAUD have the cognitive resources to learn new information and benefit from psychoeducation; and (3) psychoeducation positively impacts clinical outcomes. METHODS: We tested these assumptions in two experimental studies. In the first experiment in 66 recently detoxified patients with sAUD and 102 matched healthy controls, we measured baseline knowledge on sAUD through self-reported questionnaires, determined whether an up-to-date psychoeducation program can improve this knowledge, explored the role of cognitive abilities in such learning, and established the impact of psychoeducation on relapse rates. In a second experiment in 23 patients and 17 healthy controls, we examined whether the increased knowledge following psychoeducation is alcohol specific, and whether the motivation to change influences the relation between psychoeducation and clinical outcomes. RESULTS: At treatment entry, patients with sAUD presented with more sAUD-related knowledge than healthy controls, and were able to increase this knowledge following psychoeducation, independently of their cognitive status. However, psychoeducation did not impact either the motivation to change or relapse rates. CONCLUSIONS: Psychoeducation can increase patients' knowledge about sAUD, but it does not increase the likelihood of abstinence or controlled low consumption after discharge. Thus, clinicians should question whether psychoeducation should occupy a central position in the therapeutic programs and reconsider what can be expected from psychoeducation in terms of achieving therapeutic objectives.

A prevention program for binge drinking among students based on mindfulness and implementation intention (ALCOMEDIIT): a randomized controlled trial.

BACKGROUND: The emergence of new problematic alcohol consumption practices among young people requires new dynamics in prevention strategies. In this context, the ADUC project (Alcohol and Drugs at the University of Caen) aims to develop a better understanding of alcohol consumption, and in particular the practice of binge drinking (BD) in students, in order to develop relevant and adapted prevention tools. The ALCOMEDIIT study (Rin Normandie and IRESP funding; Agreement 20II31-00 - ADUC part 3) is a randomized controlled trial that focuses on the specific determinant of impulsivity. The main objective of this experiment is to assess a program for the prevention of BD practices based on motivational interviewing (MI) associated with implementation intention (II) and mindfulness meditation (MBM) in a student environment. METHODS: This study will include 170 healthy subjects who will be students at the university, alcohol users, with a BD score > 1 in the month preceding the inclusion but not presenting any specific disorder. The trial will be proposed by e-mail and students who meet the inclusion criteria will join either a control group which will benefit from a MI or an experimental group which will additionally benefit from an initiation to MBM with II (initial visit T0). In order to measure the effectiveness of the prevention program in terms of BD decrease, a follow-up at 1 month (T1) as well as a follow-up at 6 months (T6; exploratory) will be proposed to all participants. The total duration of this research protocol is 21 months. DISCUSSION: The purpose of this study is to evaluate the interest of associating mindfulness meditation practices and implementation of self-regulation strategies to optimize their use, with a motivational interview in an innovative prevention program aiming at reducing alcohol use and BD practice in the student population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05565989, September 30, 2022. https://clinicaltrials.gov/study/NCT05565989 Protocol version 2.0 (September 2022) No. ID-RCB: 2022-A00983-40.

Measuring craving: A systematic review and mapping of assessment instruments. What about sexual craving?

BACKGROUND AND AIMS: Craving is central in the definition of addictive disorders because of its diagnostic and prognostic value. Its measurement is essential in clinical practice. Previous reviews provided a better overview of existing instruments; however, they do not consider emerging substances and behaviors such as sexual addictions. Our objectives were threefold: (1) to provide a systematic review of craving assessment instruments and their psychometric characteristics within a transdiagnostic approach, (2) to highlight and map their conceptual relationships and (3) to identify potential sexual craving assessment instruments. METHODS: The review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The PubMed, Embase, PsychInfo and Cochrane/Central databases were searched for publications that met the following inclusion criterion: validation studies of craving assessment instruments, regardless of target substance or behavior. The original search identified 4561 references and included 147 articles. Each selected study was a peer-reviewed publication. RESULTS: This review provides a synthesis of the psychometric properties of 36 original instruments and identified 93 variations of these instruments (e.g. translations). We were able to highlight five transdiagnostic families of instruments, each corresponding to a conceptual model. Only one instrument for assessing craving in the domain of compulsive sexual behavior, focused on pornography use, has been identified: the Pornography Craving Questionnaire. CONCLUSION: This review mapped all craving assessment instruments from a transdiagnostic perspective, finding 36 original instruments and 93 variations. The evolution of instruments to measure craving mirrors the evolution of the concept of craving which has progressively integrated cognitive, conditioning and sensory dimensions, and attests to the importance of the context of assessment. Development of an instrument to measure 'sexual craving' is needed and could be based on the data from our review.

Age-related changes in fast spindle clustering during non-rapid eye movement sleep and their relevance for memory consolidation.

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 ±â€…SD: 69.3 ±â€…4.1 years) and 32 young-middle aged (34.5 ±â€…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 < .001). This effect was not mediated by NREM sleep fragmentation. The clustering level of fast spindles modulated their characteristics (p < .001). Finally, the mean size of spindle clusters was positively associated with memory consolidation (p = .036) and negatively with NREM sleep micro-arousal density (p = .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 aging, to understand the impact of age-related sleep changes on memory. 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.

Distinct Sleep Alterations in Alcohol Use Disorder Patients with and without Korsakoff's Syndrome: Relationship with Episodic Memory.

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.

Trimethylamine N-Oxide (TMAO) and Indoxyl Sulfate Concentrations in Patients with Alcohol Use Disorder.

BACKGROUND: Trimethylamine N-oxide (TMAO) and indoxyl sulfate (IS) are produced by the microbiota and the liver, and can contribute to brain aging and impaired cognitive function. This study aims to examine serum TMAO and IS concentrations in patients with alcohol-use disorder (AUD) at the entry for alcohol withdrawal, and the relationships with several biological, neuropsychological, and clinical parameters. METHODS: TMAO 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. RESULTS: 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. CONCLUSIONS: 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.

Alcohol Withdrawal Is an Oxidative Stress Challenge for the Brain: Does It Pave the Way toward Severe Alcohol-Related Cognitive Impairment?

Alcohol use is a leading cause of mortality, brain morbidity, neurological complications and minor to major neurocognitive disorders. Alcohol-related neurocognitive disorders are consecutive to the direct effect of chronic and excessive alcohol use, but not only. Indeed, patients with severe alcohol use disorders (AUD) associated with pharmacological dependence suffer from repetitive events of alcohol withdrawal (AW). If those AW are not managed by adequate medical and pharmacological treatment, they may evolve into severe AW, or be complicated by epileptic seizure or delirium tremens (DT). In addition, we suggest that AW favors the occurrence of Wernicke's encephalopathy (WE) in patients with known or unknown thiamine depletion. We reviewed the literature on oxidative stress as a core mechanism in brain suffering linked with those conditions: AW, epileptic seizure, DT and WE. Thus, we propose perspectives to further develop research projects aiming at better identifying oxidative stress brain damage related to AW, assessing the effect of repetitive episodes of AW, and their long-term cognitive consequences. This research field should develop neuroprotective strategies during AW itself or during the periwithdrawal period. This could contribute to the prevention of severe alcohol-related brain damage and cognitive impairments.

Physical activity: A promising adjunctive treatment for severe alcohol use disorder.

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.

Contribution of sleep disturbances to the heterogeneity of cognitive and brain alterations in alcohol use disorder.

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.

Temporal Cognitive and Brain Changes in Korsakoff Syndrome.

OBJECTIVE: To investigate cognitive and brain changes in patients with Korsakoff syndrome (KS) over months and up to 10 years after the diagnosis. METHODS: Two 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. RESULTS: No 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. CONCLUSION: In 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.