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The thalamus has a key role in mediating cortical-subcortical interactions but is often neglected in neuroimaging studies, which mostly focus on changes in cortical structure and activity. One of the main reasons for the thalamus being overlooked is that the delineation of individual thalamic nuclei via neuroimaging remains controversial. Indeed, neuroimaging atlases vary substantially regarding which thalamic nuclei are included and how their delineations were established. Here, we review current and emerging methods for thalamic nuclei segmentation in neuroimaging data and consider the limitations of existing techniques in terms of their research and clinical applicability. We address these challenges by proposing a roadmap to improve thalamic nuclei segmentation in human neuroimaging and, in turn, harmonize research approaches and advance clinical applications. We believe that a collective effort is required to achieve this. We hope that this will ultimately lead to the thalamic nuclei being regarded as key brain regions in their own right and not (as often currently assumed) as simply a gateway between cortical and subcortical regions., (© 2024. Springer Nature Limited.)

Alcohol use disorder is a chronic disease characterized by an inappropriate pattern of drinking, resulting in negative consequences for the individual's physical, mental and social health. Korsakoff's syndrome is a complication of alcohol use disorder and is characterized by severe memory and executive deficits. The fronto-cerebellar and Papez circuits are structurally affected in patients with alcohol use disorder with and without Korsakoff's syndrome. The first objective of the present study was to measure the effect of chronic and excessive alcohol consumption on resting-state functional connectivity of these two functional brain networks. The second objective was to identify, for the first time, resting-state functional connectivity abnormalities specific to amnesic patients with Korsakoff's syndrome. In the present study, a neuropsychological assessment and a resting-state functional magnetic resonance imaging examination were conducted in 31 healthy controls (43.6 ± 6.1 years) and 46 patients (46.6 ± 9.1 years) with alcohol use disorder including 14 patients with Korsakoff's syndrome (55.5 ± 5.3 years) to examine the effect of chronic and heavy alcohol consumption on functional connectivity of the fronto-cerebellar and the Papez circuits at rest and the specificity of functional connectivity changes in Korsakoff's syndrome compared to alcohol use disorder without Korsakoff's syndrome. The resting-state functional connectivity analyses focused on the nodes of the fronto-cerebellar and Papez circuits and combined region of interest and graph theory approaches, and whether these alterations are associated with the neuropsychological profile. In patients pooled together compared to controls, lower global efficiency was observed in the fronto-cerebellar circuit. In addition, certain regions of the fronto-cerebellar and Papez circuits were functionally hyperconnected at rest, which positively correlated with executive functions. Patients with Korsakoff's syndrome showed lower resting-state functional connectivity, lower local and global efficiency within the Papez circuit compared to those without Korsakoff's syndrome. Resting-state functional connectivity positively correlated with several cognitive scores in patients with Korsakoff's syndrome. The fronto-cerebellar and Papez circuits, two normally well-segregated networks, are functionally altered by alcohol use disorder. The Papez circuit attempts to compensate for deficits in the fronto-cerebellar circuit, albeit insufficiently as evidenced by patients' overall lower cognitive performance. Korsakoff's syndrome is characterized by altered functional connectivity in the Papez circuit known to be centrally involved in memory., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Many patients with substance use disorders (SUDs) present cognitive deficits, which are associated with clinical outcomes. Neuropsychological remediation might help rehabilitate cognitive functions in these populations, hence improving treatment effectiveness. Nardo and colleagues (Neuropsychology Review, 32, 161-191, 2022) reviewed 32 studies applying cognitive remediation for patients with SUDs. They underlined the heterogeneity and lack of quality of studies in this research field but concluded that cognitive remediation remains a promising tool for addictive disorders. We capitalize on the insights of this review to identify the key barriers that currently hinder the practical implementation of cognitive remediation in clinical settings. We outline five issues to be addressed, namely, (1) the integration of cognitive remediation in clinical practices; (2) the selection criteria and individual factors to consider; (3) the timing to be followed; (4) the priority across trained cognitive functions; and (5) the generalization of the improvements obtained. We finally propose that cognitive remediation should not be limited to classical cognitive functions but should also be extended toward substance-related biases and social cognition, two categories of processes that are also involved in the emergence and persistence of SUDs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Cocaine Use Disorder (CUD) is an important health issue, associated with structural brain abnormalities. However, the impact of the route of administration and their predictive value for relapse remain unknown., Methods: We conducted an anatomical MRI study in 55 CUD patients (26 CUD-Crack and 29 CUD-Hydro) entering inpatient detoxification, and 38 matched healthy controls. In patients, a 3-months outpatient follow-up was carried out to specify the treatment outcome status (relapser when cocaine was consumed once or more during the past month). A Voxel-Based Morphometry approach was used., Results: Compared with controls, CUD patients had widespread gray matter alterations, mostly in frontal and temporal cortices, but also in the cerebellum and several sub-cortical structures. We then compared CUD-Crack with CUD-Hydro patients and found that crack-cocaine use was associated with lower volume in the right inferior and middle temporal gyri, and the right fusiform gyrus. Cerebellar vermis was smaller during detoxification in subsequent relapsers compared to three-months abstainers., Conclusions: Patients with CUD display widespread cortical and subcortical brain shrinkage. Patients with preferential crack-cocaine use and subsequent relapsers showed specific gray matter volume deficits, suggesting that different patterns of cocaine use and different clinical outcome are associated with different brain macrostructure., Competing Interests: Declaration of competing interest All authors declared no financial disclosures or conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© 2024 Research Society on Alcohol.)

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., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

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 (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&#95;statement&#95;AGEWELL.doc in supplementary material. Registration: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Transient global amnesia is characterized by the sudden apparition of severe episodic amnesia, mainly anterograde, associated with emotional changes. Even though the symptoms are stereotyped, cerebral mechanism underlying transient global amnesia remains unexplained and previous studies using positron emission tomography do not show any clear results or consensus on cerebral regions impacted during transient global amnesia. This study included a group of 10 transient global amnesic patients who underwent 18 F-fluorodeoxyglucose positron emission tomography during the acute or recovery phase of the episode and 10 paired healthy controls. Episodic memory was evaluated with the encoding-storage-retrieval paradigm and a story recall test of the Wechsler's memory scale and anxiety was assessed with the Spielberger scale. We used statistical parametric mapping to identify modifications of whole-brain metabolism. Regarding hypometabolism, there was no brain region systematically affected in all transient global amnesic patients and the comparison between amnesic patients and controls did not show any significant differences. To better understand the specific implication of the limbic circuit in the pathophysiology of transient global amnesia, we then conducted a correlational analysis that included regions of this network. Our findings showed that in healthy controls, regions of the limbic circuit seem to operate in a synchronized way with all regions being highly correlated to each other. On the opposite, in transient global amnesic patients, we observed a clear disruption of this normal correlational patterns between regions with the medial temporal lobe (the hippocampus, parahippocampal gyrus and amygdala) included in one cluster and the orbitofrontal cortex, anterior and posterior cingulate gyrus and thalamus gathered in the other one. Given the individual variability in the time course of transient global amnesia, the direct comparison between a group of patients and controls does not seem to favour the identification of subtle and transient alterations in regional metabolism. The involvement of an extended network, such as the limbic circuit, seems more likely to explain the symptoms of patients. Indeed, the synchronization of regions within the limbic circuit seems to be altered during transient global amnesia, which could explain the amnesia and anxiety observed in transient global amnesic patients. The present study thus deepens our understanding of the mechanisms underlying not only amnesia but also the emotional component of transient global amnesia by considering it as a disruption in the normal correlational patterns within the limbic circuit., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: To assess recovery of alcohol-related neuropsychological deficits in a group of patients with pure severe alcohol use disorder (AUD) during a detoxification program using the Brief Evaluation of Alcohol-Related Neuropsychological Impairment (BEARNI) test., Methods: Thirty-two patients with severe AUD using DSM-IV criteria (24 men, mean age = 45.5 ± 6.8 years old) were assessed using the BEARNI 8 ± 2 days after alcohol cessation (T1) and then were reassessed within 18 ± 2 days after alcohol cessation (T2). The primary study endpoint was the number of patients initially impaired at T1 who recovered cognitive functions at T2 assessment., Results: At T1, 59% (n = 19) patients with pure severe AUD had at least one impaired cognitive function assessed by the BEARNI. At T2, 63% of the patients with AUD with deficits at T1 had normal BEARNI cognitive scores (χ2 = 7.7, P = 0.005); specifically, the percentages of participants with normal subtest scores were 63% on memory (χ2 = 12.4, P = 0.0004), 100% on verbal fluency (χ2 = 16; P = <0.0001), 60% on alphabetical span (χ2 = 12.8; P = 0.0003) and 67% on visuospatial (χ2 = 15, P = 0.0001)., Conclusions: The cognitive impairments of two-thirds of patients with pure AUD included in the present study recovered within 18 days of abstinence, earlier than reported in previous studies., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

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., (© 2022 Wiley Periodicals LLC.)

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., (© 2022 Society for the Study of Addiction.)

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., (© 2022. The Author(s).)

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.

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.

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 Sant&#233; 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.

The pathophysiological mechanisms behind amnesia are still unknown. Recent literature, through the study of patients with Alcohol Use Disorder with and without Korsakoff's syndrome, increasingly shows that physiological alterations to the thalamus have an important role in the development of amnesia. This review gives an overview of neuropsychological, neuropathological and neuroimaging contributions to the understanding of Korsakoff's syndrome, highlighting the central role of the thalamus in this amnesia. The thalamus being a multi-nucleus structure, the limitations regarding the loci, nature and alterations to specific nuclei are discussed, along with potential solutions. Finally, future directions for clinical research are laid out to unravel the intricacies inherent to amnesia. They consider the need to evaluate the physiological role of the thalamus, not only as an entity but also as part of a brain circuit through a more integrative approach., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Conflicts of interest The authors do not have any conflicts of interest to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver-brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: In this study, we investigated (1) the effect of chronic and excessive alcohol consumption on whole blood (WB) and serum concentrations of thiamine and its metabolites after supplementation, and (2) the relationship between the perturbations of thiamine metabolism and neuropsychological abilities. Methods: WB and serum samples were collected in patients with Alcohol Use Disorder (AUD) and in healthy control subjects (after oral thiamine supplementation, or without supplementation). Thiamine (Th), thiamine monophosphate (TMP) and thiamine diphosphate (TDP) were quantified. The Brief Evaluation of Alcohol-Related Neuropsychological Impairments (BEARNI) and the Montreal Cognitive Assessment (MoCA) were performed by each AUD participant. Based on the BEARNI score, two groups of AUD patients were studied: AUD patients with no or mild cognitive impairment (AUD COG+), and AUD patients with moderate-to-severe cognitive impairment (AUD COG-). Results: In WB, Th concentrations were significantly higher, and percentages of phosphate esters of thiamine were significantly lower in AUD COG- patients compared to controls. In serum, Th concentrations were significantly higher in AUD COG- patients compared to controls. The percentage of Th in serum was significantly higher in AUD COG- patients compared to AUD COG+ patients, and to the groups of controls. When adjusted on education level, the percentage of Th in serum in AUD patients negatively correlated with the scores at BEARNI and MoCA, and Th concentration in serum negatively correlated with MoCA. Conclusions: These data support an impairment of metabolism and/or distribution of thiamine in AUD patients, and a relationship with the development of alcohol-related cognitive deficits.

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 18 F-fluorodeoxyglucose-PET. The KS C group, recruited at Caen University Hospital, was examined early after the KS diagnosis (KS C -T1) and 1 year later (KS C -T2). The KS R group, recruited at nursing home at Roubaix, was evaluated 10 years after the diagnosis. Longitudinal comparisons in KS C explored short-term changes, while cross-sectional comparisons between KS C -T1 and KS R 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, KS C -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 KS C -T2 and KS R . Contrary to KS C at T1 and T2, KS R had preserved inhibition abilities. Atrophy was similar but less extended in KS C -T2 and even more limited in KS R . At all times, the thalamus, hypothalamus, and fornix remained severely atrophied. Hypometabolism was still widespread in KS C -T2 and KS R , notably affecting the diencephalon. Cerebellar metabolism decreased over time and normalized in KS R , 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., (© 2021 American Academy of Neurology.)

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., (© 2021 by the Research Society on Alcoholism.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Histopathological alterations of the mamillary bodies are the most conspicuous and the most consistent neuropathological features of several disorders that occur after severe thiamine deficiency, such as Wernicke's encephalopathy and Korsakoff's syndrome. Moreover, they are among the few abnormalities that are visible to the naked eye in these disorders. With a lifetime prevalence of approximately 1.3%, Wernicke's encephalopathy is by far the most frequent cause of damage to the mamillary bodies in humans. Still, there is a persisting uncertainty with regard to the development and the clinical consequences of this damage, because it is virtually impossible to study in isolation. As a rule, it always occurs alongside neuropathology in other subcortical gray matter structures, notably the medial thalamus. Converging evidence from other pathologies and animal experiments is needed to assess the clinical impact of mamillary body damage and to determine which functions can be attributed to these structures in healthy subjects. In this chapter, we describe the history and the current state of knowledge with regard to thiamine deficiency disorders and the contribution of mamillary body damage to their clinical presentations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 T 1 -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., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Neuropsychological impairments found in recently detoxified patients with alcohol use disorder (AUD) can limit the benefit of psychosocial treatments and increase the risk of relapse. These neuropsychological deficits are reversible with abstinence. The aim of this retrospective clinical study was to investigate whether a short-term stay as inpatients in a convalescent home enables neuropsychological deficits observed in recently detoxified AUD patients to recover and even performance to return to normal., Methods: Neuropsychological data were collected in 84 AUD patients. Five neuropsychological components were assessed before and after a three-week stay in a convalescent home offering multidisciplinary support. Baseline and follow-up performance were compared in the entire group of patients and in subgroups defined by the nature and intensity of the therapy (OCCASIONAL: occasional occupational and physical therapy; INTENSIVE: intensive occupational and physical therapy and neuropsychological training)., Results: In the entire group of patients, neuropsychological performance significantly improved between baseline and follow-up for all 5 components and even returned to a normal level for 4 of them. The ratio of patients with impaired performance was significantly lower at follow-up than baseline examination for 3 components in the INTENSIVE group only., Conclusion: Recently detoxified AUD patients with cognitive deficits benefit from a short-term stay in an environment ensuring sobriety and healthy nutrition. Cognitive recovery may be enhanced by intensive care including neuropsychological training. Alcohol programs could be postponed in patients with cognitive deficits in order to offer psychosocial treatment when patients are cognitively able to benefit from it., (Copyright © 2020. Published by Elsevier Ltd.)

Alcohol abuse is a major public health problem worldwide, causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated with a worse outcome for ischemic stroke patients. To study the underlying mechanisms of this deleterious effect of HD, we performed an extensive analysis of the brain inflammatory responses of mice chronically exposed or not to 10% alcohol before and after ischemic stroke. Inflammatory responses were analyzed at the parenchymal, perivascular, and vascular levels by using transcriptomic, immunohistochemical, in vivo 2-photon microscopy and molecular MRI analyses. Alcohol-exposed mice show, in the absence of any other insult, a neurovascular inflammatory priming (i.e., an abnormal inflammatory status including an increase in brain perivascular macrophages [PVM]) associated with exacerbated inflammatory responses after a secondary insult (ischemic stroke or LPS challenge). Similar to our clinical data, alcohol-exposed mice showed larger ischemic lesions. We show here that PVM are key players on this aggravating effect of alcohol, since their specific depletion blocks the alcohol-induced aggravation of ischemic lesions. This study opens potentially new therapeutic avenues aiming at blocking alcohol-induced exacerbation of the neurovascular inflammatory responses triggered after ischemic stroke.

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., Competing Interests: N. Cabé déclare faire ou avoir fait des interventions ponctuelles (actions de formation) pour les entreprises Bouchara Recordati, Indivior ; et avoir été pris en charge, à l’occasion de déplacements pour congrès, par Bouchara Recordati, Indivior, Gilead, Abbvie. A. Laniepce déclare avoir un Contrat doctoral co-financé par l’Union Européenne dans le cadre du programme ERDF-ESF 2014-2020 et la société Lundbeck. F. Vabret n'a pas fourni de déclaration de liens d'intérêts. C. Boudehent et A.-L. Pitel déclarent n'avoir aucun lien d'intérêts.

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., (© 2019 by the Research Society on Alcoholism.)

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., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Alcohol use disorder (AUD) patients without Korsakoff's syndrome (KS) report a variable self-rated sleep quality. Their ability to accurately judge their sleep quality may be related to their alcohol-related cognitive deficits and brain damage. KS patients, who present severe brain dysfunction, may be cognitively unable to judge their sleep quality. The aim of the present study is to examine, in AUD and KS patients, whether the absence of sleep complaint is associated with altered brain structure and impaired cognitive abilities within specific cerebral networks., Methods: An assessment of subjective sleep quality was conducted in 20 healthy controls, 37 AUD patients, and 17 KS patients. Patients were first pooled together and then classified into 2 groups (no-complaint AUD + KS and complaint AUD + KS ) according to the total Pittsburg Sleep Quality Index score. Cognitive scores, gray matter (GM) volume, and white matter (WM) integrity were compared between these 2 groups, and then in AUD and KS patients separately., Results: Poor sleep quality was reported by 70% of AUD and 18% of KS patients. Compared to controls, both no-complaint AUD + KS and complaint AUD + KS presented cortical and subcortical alterations as well as episodic memory deficits, which were more severe in patients without sleep complaint. Only no-complaint AUD + KS presented executive deficits. Then, considering the clinical diagnosis, GM volume in frontotemporal regions, WM integrity, and executive functions were affected to the same extent in AUD and KS patients without sleep complaint., Conclusions: Our results confirm the high prevalence of sleep complaint in AUD patients and the rare complaint in KS patients. In AUD and KS patients, the absence of sleep complaint may not indicate good sleep quality but rather reflect executive deficits and frontothalamic damage. Alcohol-related cognitive deficits may indeed alter the ability to self-evaluate sleep quality, suggesting that the use of sleep questionnaire should be considered with caution in patients with executive deficits., (© 2019 by the Research Society on Alcoholism.)

The function of the human mediodorsal thalamic nucleus (MD) has so far eluded a clear definition in terms of specific cognitive processes and tasks. Although it was at first proposed to play a role in long-term memory, a set of recent studies in animals and humans has revealed a more complex, and broader, role in several cognitive functions. The MD seems to play a multifaceted role in higher cognitive functions together with the prefrontal cortex and other cortical and subcortical brain areas. Specifically, we propose that the MD is involved in the regulation of cortical networks especially when the maintenance and temporal extension of persistent activity patterns in the frontal lobe areas are required., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

After a traumatic brain injury (TBI), behavioral disorders can occur without major focal brain lesion, and in these situations, their pathophysiology remains unclear. The aim of this study is to examine whether TBI patients with behavioral disorders but without any focal damage, as observed from an initial clinical CT scan, present subtle volumetric alterations that could be measured voxel-by-voxel in the whole brain with MRI. Eight male adults with severe TBI who had behavioral sequela but not major focal cerebral lesion and 17 age-matched controls underwent a volumetric T1-weighted 1.5T MRI. A two step analysis was performed. First, gray matter (GM) and white matter (WM) volumes were compared between groups using voxel-based morphometry. Second, we examined brain regions systematically damaged using the sum of the individual binary maps obtained from z-maps thresholded at -1.75 for significant GM and WM atrophy. TBI patients had lower GM volume than controls (p < 0.001, uncorrected) in the right parahippocampal gyrus; left and right superior, middle, and inferior temporal gyri; left superior frontal gyrus; right middle frontal gyrus; thalami; mammillary bodies; caudate nuclei; insulae; cerebellar cortex; and vermis. WM volume was lower (p < 0.001, uncorrected) in the TBI group than in controls in the periventricular area and around the basal nuclei. We found shrinkage in the dorsomedial thalami in each of the TBI patients, and in the posterior part of the right putamen and caudate nuclei in seven TBI patients. Shrinkage in the dorsomedial thalami and in the posterior part of the right putamen and caudate nuclei may be a common effect of the disseminated microscopic lesions, and be associated with behavioral issues in severe TBI patients without major focal lesions.

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., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Decoding emotional information from faces and voices is crucial for efficient interpersonal communication. Emotional decoding deficits have been found in alcohol-dependence (ALC), particularly in crossmodal situations (with simultaneous stimulations from different modalities), but are still underexplored in Korsakoff syndrome (KS). The aim of this study is to determine whether the continuity hypothesis, postulating a gradual worsening of cognitive and brain impairments from ALC to KS, is valid for emotional crossmodal processing., Methods: Sixteen KS, 17 ALC and 19 matched healthy controls (CP) had to detect the emotion (anger or happiness) displayed by auditory, visual or crossmodal auditory-visual stimuli. Crossmodal stimuli were either emotionally congruent (leading to a facilitation effect, i.e. enhanced performance for crossmodal condition compared to unimodal ones) or incongruent (leading to an interference effect, i.e. decreased performance for crossmodal condition due to discordant information across modalities). Reaction times and accuracy were recorded., Results: Crossmodal integration for congruent information was dampened only in ALC, while both ALC and KS demonstrated, compared to CP, decreased performance for decoding emotional facial expressions in the incongruent condition., Conclusions: The crossmodal integration appears impaired in ALC but preserved in KS. Both alcohol-related disorders present an increased interference effect. These results show the interest of more ecological designs, using crossmodal stimuli, to explore emotional decoding in alcohol-related disorders. They also suggest that the continuum hypothesis cannot be generalised to emotional decoding abilities.

Background: Alcohol-dependence is related to large-scale cognitive impairments, particularly for executive functions (EF). These deficits persist even after long-term abstinence and have a major impact on patients' everyday life and relapse risk. Earlier studies, based on multi-determined tasks, mostly focused on inhibition and did not offer a theoretically-grounded and exhaustive view of the differential deficit across EF. The present paper proposes a model-based exploration of EF in alcohol-dependent individuals (ALC), to precisely compare the specific deficit related to each executive subcomponent., Methods: Forty-seven recently detoxified ALC were compared to 47 matched healthy participants on a nine-tasks validated neuropsychological battery, simultaneously exploring and comparing the three main executive subcomponents (shifting, updating, and inhibition). Psychopathological comorbidities were also controlled for., Results: Reaction time indexes revealed a global slowing down among ALC, whatever the EF explored. Accuracy indexes revealed a moderate deficit for inhibition tasks but a massive impairment for shifting and updating ones. Complementary analyses indicated that the executive deficits observed were centrally related to alcohol-dependence, while comorbid depressive symptoms appeared to intensify the deficits observed., Conclusions: By offering a direct comparison between the three major EF, these results showed that alcohol-related executive deficits extend beyond the classically described inhibition impairment. This impairment encompasses each EF subcomponent, as ALC actually presented stronger deficits for updating and shifting abilities. This first observation of a multifaceted EF deficit stresses the need for an individualized evaluation and rehabilitation of EF during and/or after the detoxification process., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Korsakoff syndrome (KS), most frequently resulting from alcohol dependence (ALC), is characterized by severe anterograde amnesia. It has been suggested that these deficits may extend to other memory components, and notably source memory deficits involved in the disorientation and temporal confusion frequently observed in KS. However, the extent of this source memory impairment in KS and its usefulness for the differential diagnosis between ALC and KS remain unexplored., Methods: Nineteen patients with KS were compared with 19 alcohol-dependent individuals and 19 controls in a source memory test exploring temporal context confusions ("continuous recognition task"). Episodic memory and psychopathological comorbidities were controlled for., Results: While no source memory deficit was observed in ALC, KS was associated with a significant presence of temporal context confusion, even when the influence of comorbidities was taken into account. This source memory impairment did not appear to be related to performances on episodic memory or executive functions., Conclusions: Patients with KS displayed source memory deficits, as indexed by temporal context confusions. The absence of a relationship with episodic memory performances seems to indicate that source memory impairment is not a mere by-product of amnesia. As ALC was associated with preserved source memory, the presence of temporal context confusion may serve as a complementary tool for the differential diagnosis between ALC and KS., (Copyright © 2017 by the Research Society on Alcoholism.)

Gray matter (GM) lobar atrophy and glucose hypometabolism are well-described hallmarks of frontotemporal lobar degeneration (FTLD), but the relationships between them are still poorly understood. In this study, we aimed to show the patterns of GM atrophy and hypometabolism in a sample of 15 patients with the behavioral variant of FTLD (bv-FTD), compared to 15 healthy controls, then to provide a direct comparison between GM atrophy and hypometabolism, using a voxel-based method specially designed to statistically compare the two imaging modalities. The participants underwent structural magnetic resonance imaging and 18 F-fluorodeoxyglucose (FDG) positron emission tomography examinations. First, between-group comparisons of GM volume and metabolism were performed. Then, in the patient group, correlations between regional alterations and direct between-modality voxelwise comparison were performed. Finally, we examined individual patterns of brain abnormalities for each imaging modality and each patient. The observed patterns of GM atrophy and hypometabolism were consistent with previous studies. We found significant voxelwise correlations between changes in GM and FDG uptake, mainly in the frontal cortex, corresponding to the typical profile of alterations in bv-FTD. The direct comparison revealed regional variability in the relationship between hypometabolism and atrophy. This analysis revealed greater atrophy than hypometabolism in the right putamen and amygdala, and left insula and superior temporal gyrus, whereas hypometabolism was more severe than GM atrophy in the left caudate nucleus and anterior cingulate cortex. Finally, GM atrophy affected the right amygdala/hippocampus and left insula in 95 % of the patients. These findings provide evidence for regional variations in the hierarchy of hypometabolism and GM atrophy and the relationships between them, and enhance our understanding of the pathophysiology of bv-FTD.

Alcohol-related neuropsychological deficits result from chronic and excessive alcohol consumption and are associated with structural and functional damage of Papez's circuit and frontocerebellar circuit. Alcohol-related cognitive deficits are heterogeneous but especially affect executive functions and memory abilities. They result in difficulties to change alcohol behavior combined with a tendency for patients to overestimate their capacity to succeed. Alcohol-related cognitive deficits could be a risk-factor for relapse since they hamper patients to benefit fully from treatment (especially when based on relapse prevention). Screening tools usable by non-psychologists are available and can be completed by an extensive neuropsychological examination conducted by a neuropsychologist when necessary. Alcohol treatment should be adjusted to take alcohol-related cognitive deficits into account, by promoting longer treatment in healthy environment for example. Improvements of alcohol treatment options, including specific neuropsychological rehabilitation, are required for patients with persistent alcohol-related cognitive deficits., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The effects of alcoholism on cognitive and motor functioning are heterogeneous. While the role of some factors (patterns of alcohol consumption, eating habits or associated liver disease) has been hypothesized, the origins of this heterogeneity remain difficult to establish. The goals of the present study were thus to identify the clinical and biological risk factors for alcohol-related neuropsychological impairments and to determine the threshold beyond which these risk factors can be considered significant. Thirty alcoholic patients and 15 healthy controls had a blood test and underwent a neuropsychological examination. Alcohol severity measures, and liver, thiamine and malnutrition variables, were included in logistic regression models to determine the risk factors for cognitive and motor impairments (executive functions, visuospatial abilities, verbal episodic memory, ataxia), as well as those related to the severity of patients' overall neuropsychological profile (moderate or severe impairments). Liver fibrosis was found to be a risk factor for executive impairments and also for ataxia, when it was associated with long-term alcohol misuse and symptoms of withdrawal. Altered thiamine metabolism was solely predictive of verbal episodic memory impairments. This combination of biological abnormalities was associated with a profile of moderate neuropsychological impairments. Malnutrition was associated with a profile of more severe impairments. Malnutrition, altered liver function and thiamine metabolism explain, at least partially, the heterogeneity of alcohol-related neuropsychological impairments. Our findings could allow clinicians to identify patients at particular risk of severe neuropsychological impairments before the onset of irreversible and debilitating neurological complications., Competing Interests: The authors have declared that no competing interests exist.

Alcoholism is associated with widespread brain structural abnormalities affecting mainly the frontocerebellar and the Papez's circuits. Brain glucose metabolism has received limited attention, and few studies used regions of interest approach and showed reduced global brain metabolism predominantly in the frontal and parietal lobes. Even though these studies have examined the relationship between grey matter shrinkage and hypometabolism, none has performed a direct voxel-by-voxel comparison between the degrees of structural and metabolic abnormalities. Seventeen alcoholic patients and 16 control subjects underwent both structural magnetic resonance imaging and (18)F-2-fluoro-deoxy-glucose-positron emission tomography examinations. Structural abnormalities and hypometabolism were examined in alcoholic patients compared with control subjects using two-sample t-tests. Then, these two patterns of brain damage were directly compared with a paired t-test. Compared to controls, alcoholic patients had grey matter shrinkage and hypometabolism in the fronto-cerebellar circuit and several nodes of Papez's circuit. The direct comparison revealed greater shrinkage than hypometabolism in the cerebellum, cingulate cortex, thalamus and hippocampus and parahippocampal gyrus. Conversely, hypometabolism was more severe than shrinkage in the dorsolateral, premotor and parietal cortices. The distinct profiles of abnormalities found within the Papez's circuit, the fronto-cerebellar circuit and the parietal gyrus in chronic alcoholism suggest the involvement of different pathological mechanisms., (© The Author(s) 2015.)

This perspective aims at underlining the usefulness of event-related potentials (ERP) to better understand the brain correlates of Korsakoff's syndrome (KS), a neuropsychiatric disease characterized by severe memory impairment and most frequently resulting as a neurological complication of alcohol-dependence (AD). While ERP have been broadly used in AD, it has up to now been very little applied in KS or in the comparison of KS and AD. Within the framework of dual-process models, an influential theory postulating that addictive states result from an imbalance between under-activated reflective system and over-activated automatic-affective one, this paper proposes: (1) a brief synthesis of the main results of ERP studies in AD and KS, and (2) new research avenues using ERP to identify the electrophysiological correlates of cognitive and emotional dysfunction in KS. These experimental perspectives aim at exploring the continuity hypothesis, which postulates a gradient of impairments from AD to KS. We conclude on the possibility of developing neuropsychological strategies with electrophysiological follow-up to ensure KS diagnosis and test the efficacy of patient's neurocognitive rehabilitation.

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., (Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Alcohol-related neuropsychological impairments mainly affect episodic memory, working memory, and visuospatial abilities, as well as executive and motor functioning. These impairments can prevent alcoholic patients (ALs) early in abstinence from benefiting fully from treatment and reduce their ability to remain abstinent. A neuropsychological assessment seems essential for making the relevant clinical decisions. However, very few alcohol treatment departments have the financial and human resources needed to conduct an extensive neuropsychological examination of each AL. The goal of this study was therefore to assess the validity and the psychometric properties of the Brief Evaluation of Alcohol-Related Neuropsychological Impairments (BEARNI), a new screening tool especially designed to assess alcohol-related neuropsychological impairments., Methods: A total of 254 healthy controls (HCs) completed the BEARNI, and 58 of them also performed an extensive neuropsychological battery. Seventy-three ALs underwent both the BEARNI and the neuropsychological battery. This extensive neuropsychological battery of proven classification accuracy served as the reference (i.e., gold standard) for determining the ALs' cognitive status., Results: An exploratory factor analysis validated the BEARNI's underlying structure, highlighting 5 factors that reflected visuospatial abilities, executive functions, ataxia, verbal episodic memory, and verbal working memory. The standardization of each BEARNI subtest and the 2 total scores revealed that this test has sufficient diagnostic accuracy for the detection of ALs with cognitive and motor impairments., Conclusions: This study indicates that the BEARNI is a useful screening tool in clinical settings for detecting ALs' motor and cognitive impairments., (Copyright © 2015 by the Research Society on Alcoholism.)

Measurement of synaptic activity by Positron Emission Tomography (PET) and its relation to cognitive functions such as episodic memory, working memory and executive functions in healthy humans and patients with neurocognitive disorders have been well documented. In this review, we introduce the concept of PET imaging that allows the observation of a particular biological process in vivo through the use of radio-labelled compounds, its general use to the medical world and its contributions to the understanding of memory systems. We then focus on [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG-PET), the radiotracer that is used to measure local cerebral metabolic rate of glucose that is indicative of synaptic activity in the brain. FDG-PET at rest has been at the forefront of functional neuroimaging over the past 3 decades, contributing to the understanding of cognitive functions in healthy humans and how these functional patterns change with cognitive alterations. We discuss methodological considerations that are important for optimizing FDG-PET imaging data prior to analysis. We then highlight the contribution of FDG-PET to the understanding of the patterns of functional differences in non-degenerative pathologies, normal ageing, and age-related neurodegenerative disorders. Through reasonable temporal and spatial resolution, its ability to measure synaptic activity in the whole brain, independently of any specific network and disease, makes it ideal to observe regional functional changes associated with memory impairment.

Two brain networks are particularly affected by the harmful effect of chronic and excessive alcohol consumption: the circuit of Papez and the frontocerebellar circuit, in both of which the thalamus plays a key role. Shrinkage of the thalamus is more severe in alcoholics with Korsakoff's syndrome (KS) than in those without neurological complication (AL). In accordance with the gradient effect of thalamic abnormalities between AL and KS, the pattern of brain dysfunction in the Papez's circuit results in anterograde amnesia in KS and only mild-to-moderate episodic memory disorders in AL. On the opposite, dysfunction of the frontocerebellar circuit results in a similar pattern of working memory and executive deficits in the AL and KS. Several hypotheses, mutually compatible, can be drawn to explain that the severe thalamic shrinkage observed in KS has different consequences in the neuropsychological profile associated with the two brain networks., (Copyright © 2014. Published by Elsevier Ltd.)

Alcohol dependence results in two different clinical forms: "uncomplicated" alcoholism (UA) and Korsakoff's syndrome (KS). Certain brain networks are especially affected in UA and KS: the frontocerebellar circuit (FCC) and the Papez circuit (PC). Our aims were (1) to describe the profile of white matter (WM) microstructure in FCC and PC in the two clinical forms, (2) to identify those UA patients at risk of developing KS using their WM microstructural integrity as a biomarker. Tract-based spatial statistics and nonparametric voxel-based permutation tests were used to compare diffusion tensor imaging (DTI) data in 7 KS, 20 UA, and 14 healthy controls. The two patient groups were also pooled together and compared to controls. k-means classifications were then performed on mean fractional anisotropy values of significant clusters across all subjects for two fiber tracts from the FCC (the middle cerebellar peduncle and superior cerebellar peduncle) and two tracts from the PC (fornix and cingulum). We found graded effects of WM microstructural abnormalities in the PC of UA and KS. UA patients classified at risk of developing KS using fiber tracts of the PC from DTI data also had the lowest scores of episodic memory. That finding suggests that WM microstructure could be used as a biomarker for early detection of UA patients at risk of developing KS., (© 2015 Wiley Periodicals, Inc.)

Alcohol consumption patterns and recognition of health outcomes related to hazardous drinking vary widely internationally, raising the question whether these national differences are reflected in brain damage observed in alcoholism. This retrospective analysis assessed variability of alcoholism's effects on brain cerebrospinal fluid (CSF) and white matter volumes between France and the United States (U.S.). MRI data from two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) were acquired on 1.5T imaging systems in 287 controls, 165 uncomplicated alcoholics (ALC), and 26 alcoholics with Korsakoff's Syndrome (KS). All data were analyzed at the U.S. site using atlas-based parcellation. Results revealed graded CSF volume enlargement from ALC to KS and white matter volume deficits in KS only. In ALC from France but not the U.S., CSF and white matter volumes correlated with lifetime alcohol consumption, alcoholism duration, and length of sobriety. MRI highlighted CSF volume enlargement in both ALC and KS, serving as a basis for an ex vacuo process to explain correlated gray matter shrinkage. By contrast, MRI provided a sensitive in vivo biomarker of white matter volume shrinkage in KS only, suggesting a specific process sensitive to mechanisms contributing to Wernicke's encephalopathy, the precursor of KS. Identified structural brain abnormalities may provide biomarkers underlying alcoholism's heterogeneity in and among nations and suggest a substrate of gray matter tissue shrinkage. Proposed are hypotheses for national differences in interpreting whether the severity of sequelae observe a graded phenomenon or a continuum from uncomplicated alcoholism to alcoholism complicated by KS.