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CORK Bibliography: Alcohol, Chronic Effects

31 citations. 2011 to present

Prepared: June 2012

Abraham J; Balbo S; Crabb D; Brooks PJ. Alcohol metabolism in human cells causes DNA damage and activates the Fanconi Anemia-breast cancer susceptibility (FA-BRCA) DNA damage Response Network. Alcoholism: Clinical and Experimental Research 35(12): 2113-2120, 2011. (36 refs.)

Background: We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemiabreast cancer susceptibility (FA-BRCA) DNA damage response network. Methods: To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA-BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B. Results: Incubation of HeLa-ADH1B cells with ethanol (20 mM) resulted in acetaldehyde accumulation in the media, which was prevented by co-incubation with 4-methyl pyrazole (4-MP), a specific inhibitor of ADH. Ethanol treatment of HeLa-ADH1B cells produced a 4-fold increase in the acetaldehyde-DNA adduct and N 2-ethylidene-dGuo and also resulted in the activation of the FA-BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4-MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking. Conclusions: Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network.

Brizer D; Castandea R, eds. Clinical Addiction Psychiatry. New York: Cambridge University Press, 2011. (Chapter refs.)

This book is described as an anthology of essays setting forth the most current and authoritative information on addiction theory, practice and research. Each chapter is authored by a recognized authority in the field. The volume covers diverse material, from the environment, to genetics, culture and spirituality, treatment and pharmacology. The book, with 24 essays, is organized in three parts. Part I sets forth basic constructs of addiction medicine. This includes discussion of the disease concept, abstinence as a treatment goal, medical sequelae of addiction, the relationship of substance use and suicide. psychotherapeutic paradigms, and drug therapies. Part II focuses upon "the real world." It includes twelve step approaches; nicotine addiction and smoking cessation; managing alcoholism in primary care; methadone treatment; prescription drug abuse. Part III considers special topics, such as pain management and addiction treatment; neurofeedback; drug therapies for alcohol dependence; emergency medical presentation; acupuncture; and EEG neurofeedback therapy.

Buhler M; Mann K. Alcohol and the human brain: A systematic review of different neuroimaging methods. (review). Alcoholism: Clinical and Experimental Research 35(10): 1771-1793, 2011. (184 refs.)

Background: Imaging techniques have been in widespread use in the scientific community for more than 3 decades. They facilitate noninvasive, in vivo studies of the human brain in both healthy and diseased persons. These brain-imaging techniques have contributed significantly to our understanding of the effects of alcohol abuse and dependence on structural and functional changes in the human brain. A systematic review summarizing these contributions has not previously been conducted, and this is the goal of the current paper. Methods: The databases PubMedicine, PsycINFO, and PSYNDEX were searched using central key words. Fulfilling the inclusion criteria were 140 functional and structural imaging studies, together comprising data from more than 7,000 patients and controls. The structural imaging techniques we considered were cranial computerized tomography and various magnetic resonance imaging-based techniques, including voxel-based morphometry, deformation-based morphometry, diffusion tensor magnetic resonance imaging, and diffusion-weighted magnetic resonance imaging. The functional methods considered were magnetic resonance spectroscopy, positron emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging. Results: Results from studies using structural imaging techniques have revealed that chronic alcohol use is accompanied by volume reductions of gray and white matter, as well as microstructural disruption of various white matter tracts. These changes are partially reversible following abstinence. Results from functional imaging methods have revealed metabolic changes in the brain, lower glucose metabolism, and disruptions of the balance of neurotransmitter systems. Additionally, functional imaging methods have revealed increased brain activity in the mesocorticolimbic system in response to alcohol-themed pictures relative to nondrug-associated stimuli, which might be of predictive value with regard to relapse. Conclusions: There has been tremendous progress in the development of imaging technologies. Use of these technologies has clearly demonstrated the structural and functional brain abnormalities that can occur with chronic alcohol use. The study of the alcoholic brain provides an heuristic model which furthers our understanding of neurodegenerative changes in general, as well as their partial reversibility with sustained abstinence. Additionally, functional imaging is poised to become an important tool for generating predictions about individual brain functioning, which can then be used as a basis for personalized medicine.

Butman S. In-stent restenosis: While not exactly about smoking, it so often is about smoking. (editorial). Catheterization and Cardiovascular Interventions 78(4): 609-610, 2011. (7 refs.)

Chanraud S; Pitel AL; Pfefferbaum A; Sullivan EV. Disruption of functional connectivity of the default-mode network in alcoholism. Cerebral Cortex 21(10): 2272-2281, 2011. (68 refs.)

The default mode network (DMN) comprises brain structures maximally active at rest. Disturbance of network nodes or their connections occurs with some neuropsychiatric conditions and may underlie associated dysfunction. DMN connectivity has not been examined in alcoholism, which is marked by compromised DMN nodes and impaired spatial working memory. To test whether performance would be related to DMN integrity, we examined DMN functional connectivity using functional magnetic resonance imaging (fMRI) data and graph theory analysis. We assumed that disruption of short paths between network nodes would attenuate processing efficiency. Alcoholics and controls were scanned at rest and during a spatial working memory task. At rest, the spontaneous slow fluctuations of fMRI signals in the posterior cingulate and cerebellar regions in alcoholics were less synchronized than in controls, indicative of compromised functional connectivity. Graph theory analysis indicated that during rest, alcoholics had significantly lower efficiency indices than controls between the posterior cingulate seed and multiple cerebellar sites. Greater efficiency in several connections correlated with longer sobriety in alcoholics. During the task, on which alcoholics performed on par with controls, connectivity between the left posterior cingulate seed and left cerebellar regions was more robust in alcoholics than controls and suggests compensatory networking to achieve normal performance.

Chen CH; Walker J; Momenan R; Rawlings R; Heilig M; Hommer DW. Relationship between liver function and brain shrinkage in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research 36(4): 625-632, 2012. (51 refs.)

Background: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence. Methods: We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as hematocrit (Hct) and albumin were assayed shortly after admission. Magnetic resonance imaging examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. Results: Patients with alcohol dependence had lower BV, and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), brain ratio (BR), and higher cerebrospinal fluid ratio ratio (CSFR) compared with their healthy counterparts. Age and sex were significantly correlated with some BV measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with BV indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage. Conclusions: Our results showed that the higher levels of liver function indices, especially GGT, correlated with BV shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.

Coullaut-Valera R; del Rio IAD; de Arrue-Ruiloba R; Coullaut-Valera J; Bajo-Breton R. Cognitive deterioration associated with the use of different psychoactive substances. Actas Espanolas de Psiquiatria 39(3): 168-173, 2011. (22 refs.)

Introduction. The study of the neuropsychological deficits associated with substance abuse has become highly relevant in recent years due to the serious impact they have on the physical and mental health of users. Methodology. The possible memory deficits and deterioration of executive functions were studied in a sample of 54 subjects undergoing drug detoxification and rehabilitation. Several neuropsychological tests were applied (Wechsler Memory Scale, Wisconsin Card Sorting Test, Stroop Test, Verbal Fluency Test and the Trail-Making Test). Results. Subjects with a more prolonged history of alcohol and/or cannabis use had a greater deficit in working memory. Subjects with prolonged cannabis use also showed greater deficiencies in immediate, or short-term, memory and better conserved long-term memory, as well as less interference capacity, i.e., less inhibition of automatic responses. They also had impaired alternating attention and needed more time to execute activities that required logical and sequential thought. The study also reflected the importance of duration of use as a significant variable in the increase in memory deficits. Conclusions. The duration and type of substance abuse are determinants in drug-induced cerebral deterioration.

Danker H; Keszte J; Singer S; Thoma J; Taschner R; Brahler E et al. Alcohol consumption after laryngectomy. Clinical Otolaryngology 36(4): 336-344, 2011. (32 refs.)

Objective: The aim of the study was the analysis of drinking behaviour in laryngectomised patients and its concomitants in quality of life and mental health. Study design: Multi-centered cross-sectional study. Participants and setting: Two hundred and twenty-five laryngectomised patients were asked to participate in the study. One hundred and seventy nine patients (80%) were interviewed after laryngectomy at six different ENT clinics in Germany. Main outcome measures: 'Questionnaire of Health Behaviour' (FEG), 'Short Questionnaire of Alcohol Risk', Hospital Anxiety and Depression Scale (HADS), Hornheider Questionnaire (HFB), Visual Analogue Scales (VAS) and the Quality of Life Questionnaires of the European Organization of Research and Treatment of Cancer (EORTC) (EORTC QLQ-C30, EORTC QLQ-H & N35). Results: Alcohol dependence was found in 7% of the patients. Half of the respondents showed a constant consumption of alcohol with 6% of the patients who wanted to change their consumption. Patients with alcohol dependence indicated in comparison with non-dependent persons increased anxiety (p = 0.03), problems in coping with illness (p = 0.03), increased psychosocial care needs (p = 0.02), fatigue (p = 0.04), shortness of breath (p = 0.04), diarrhoea (p = 0.02) and a worse emotional functioning level (p = 0.03). Alcohol intake was independent of tumour stage (p = 0.48), employment status (p = 0.54), social class (p = 0.82), the time interval since laryngectomy (p = 0.64) and type of voice substitute (p = 0.76). The quality of life and mental state were independent of the amount of alcohol consumed. Conclusions: The results show that alcohol dependence is associated with adverse psychosocial and medical consequences, which require treatment. Socio-demographic and medical parameters do not allow any conclusions to alcoholism risk. Therefore, an individual exploration of the patients' drinking behaviour is needed, which could prepare the ground to specific treatment.

Demirakca T; Ende G; Kammerer N; Welzel-Marquez H; Hermann D; Heinz A et al. Effects of alcoholism and continued abstinence on brain volumes in both genders. Alcoholism: Clinical and Experimental Research 35(9): 1678-1685, 2011. (30 refs.)

Background: Alcohol abuse has detrimental effects on cerebral function, metabolism, and volume. Some of these effects were found to be at least partially reversible with continued abstinence. Furthermore, it has been reported that there are different effects of alcohol on brain volumes for women compared with men, but the results concerning the interaction between alcohol dependence and gender are inconsistent. With this study, we aimed to further investigate this question by examining the global gray matter (GM) and white matter (WM) changes as well as regional and local GM changes detected by voxel-based morphometry (VBM) in male and female alcoholic patients a few weeks after detoxification and the corresponding changes in a subgroup of these patients 3 months later. Methods: A total of 50 patients, consecutively admitted for alcohol withdrawal treatment, participated in this study and were followed up for at least 3 months into abstinence. High-resolution structural images were processed with SPM8 using an optimized VBM protocol. Results: Global cerebrospinal fluid (CSF) volume was increased and WM and GM volume decreased equally in male and female patients. A gender by diagnosis interaction was found neither for global nor for regional volumes or VBM data. VBM whole brain analysis yielded a significant GM volume loss in the patient group in the cingulate gyrus and the insula in both hemispheres. Region of interest analysis for the initial and 3 months follow-up scans yielded significant gains in regional volumes, particularly the cingulate gyrus and the insula in the group of abstinent patients, whereas no volume change at all is found in the patients who had relapsed. Conclusions: Our study confirms widespread cerebral volume loss in recently detoxified alcoholics. The effects of alcohol dependence seem to have equally adverse effects on brain morphometry in males and females.

Duka T; Trick L; Nikolaou K; Gray MA; Kempton MJ; Williams H et al. Unique brain areas associated with abstinence control are damaged in multiply detoxified alcoholics. Biological Psychiatry 70(6): 545-552, 2011. (47 refs.)

Background: The ability to abstain from drinking, despite incentives to imbibe, is essential to recovery from alcoholism. Methods: We used an incentive conflict task to investigate ability to abstain from responding during presentations of incentive cues. Both alcoholic (n = 23) and healthy subjects (n = 22) were required to withhold responding during the simultaneous presentation of two visual stimuli in which the individual presentation allowed responding for monetary reward. Brain structures activated during performance of the task were studied using functional magnetic resonance imaging in healthy volunteers (n = 8), and changes in gray matter volume were studied in a separate group of patients (n = 29) compared with control subjects (n = 31) in regions of interest identified on functional magnetic resonance imaging. Results: Abstinent alcoholic patients were severely impaired on the incentive conflict task. The impairment was greater in patients with experience of several versus a single detoxification. Healthy volunteers, during the same incentive conflict task, showed distinct patterns of brain activation (including gyrus rectus, ventromedial prefrontal cortex, and superior frontal gyrus). Reduction of gray matter volume in ventromedial prefrontal cortex and superior frontal gyrus of patients was more extensive in those with multiple detoxifications. Conclusions: Performance deficits in alcoholics are associated with withdrawal-induced impairments in prefrontal subfields, which are exacerbated following repeated episodes of detoxification. Detoxification thus compromises functional and structural integrity of prefrontal cortex and may thus impair the ability to control future drinking. Performance in the incentive conflict task is a sensitive biomarker for such deficits.

Fahlke C; Berggren U; Berglund KJ; Zetterberg H; Blennow K; Engel JA et al. Neuroendocrine assessment of serotonergic, dopaminergic, and noradrenergic functions in alcohol-dependent individuals. Alcoholism: Clinical and Experimental Research 36(1): 97-103, 2012. (38 refs.)

Background: Alcohol dependence has been associated with reduced function of serotonin, dopamine as well as noradrenaline activities in several neuroendocrine studies. To our knowledge, there is, however, no study investigating all these 3 systems with the use of neuroendocrine methods in one and the same alcohol-dependent individual. Methods: Alcohol-dependent individuals (n = 42) and controls (n = 28) participated in the neuroendocrine test series. Central serotonergic neurotransmission was assessed by the prolactin (PRL) response to citalopram (CIT). The postsynaptic DRD2 function was measured by the growth hormone (GH) response to apomorphine (APO) and the postsynaptic alpha 2-adrenoceptor function by GH response to clonidine (CLON). Results: In the alcohol-dependent individuals, the PRL concentrations were significantly lower at the time points 240 minutes and 300 minutes after CIT administration and mean delta PRL value was significantly reduced by 45% in comparison with controls. There were no significant differences in APO-GH and CLON-GH concentrations at any time points or in mean delta GH values between the groups. An impaired monoaminergic profile, including all 3 systems, was significantly more frequent in alcohol-dependent individuals than controls (43% vs. 6% respectively). Conclusions: The monoaminergic dysfunction was restricted to an impairment of the serotonergic system, suggesting that this system is especially vulnerable to long-term and excessive alcohol consumption. Moreover, impaired monoaminergic profiles, including low responses in 2 or 3 systems, were more frequently observed in alcohol-dependent individuals than in controls. Such impaired profiles may be of clinical importance, but further studies are needed.

Fini M; Giavaresi G; Salamanna F; Veronesi F; Martini L; De Mattei M et al. Harmful lifestyles on orthopedic implantation surgery: a descriptive review on alcohol and tobacco use. (review). Journal of Bone and Mineral Metabolism 29(6): 633-644, 2011. (74 refs.)

Alcohol abuse and smoking habits have adverse effects on bone health and are a risk factor for osteoporosis, fractures and impaired fracture repair. Osteointegration processes around implanted biomaterials involve a coordinated cascade of complex events that are very similar to those occurring during fracture repair and require a suitable microenvironment and the coordinated action of cells and signal molecules. Therefore, diseases and harmful lifestyles that impair the normal bone healing process can reduce the success of implant surgery and may negatively influence the osteointegration of prostheses and implant devices for fracture fixation such as screws, nails and plates. Understanding the effects of harmful lifestyles on bone implant osteointegration is important for successful implant therapy, orthopedic reconstructive surgery and tissue-engineered-based therapies. However, the mechanisms by which smoking and alcoholism affect bone metabolism, bone mass and the balance of bone resorption and formation, also in the presence of an orthopedic implant, are not completely understood and remain inadequately elucidated. This review aims to analyze in vitro and in vivo studies regarding orthopedic implant integration in the presence of tobacco smoking and alcohol consumption with a focus on pathophysiology and local or systemic mechanisms of action on bone.

Foltran F; Gregori D; Franchin L; Verduci E; Giovannini M. Effect of alcohol consumption in prenatal life, childhood, and adolescence on child development. (review). Nutrition Reviews 69(11): 642-659, 2011. (256 refs.)

The effects of alcohol consumption in adults are well described in the literature, while knowledge about the effects of alcohol consumption in children is more limited and less systematic. The present review shows how alcohol consumption may negatively influence the neurobiological and neurobehavioral development of humans. Three different periods of life have been considered: the prenatal term, childhood, and adolescence. For each period, evidence of the short-term and long-term effects of alcohol consumption, including neurodevelopmental effects and associations with subsequent alcohol abuse or dependence, is presented.

Fortier CB; Leritz EC; Salat DH; Venne JR; Maksimovskiy AL; Williams V et al. Reduced cortical thickness in abstinent alcoholics and association with alcoholic behavior. Alcoholism: Clinical and Experimental Research 35(12): 2193-2201, 2011. (47 refs.)

Background: Chronic misuse of alcohol results in widespread damage to the brain. Prior morphometric studies have examined cortical atrophy in individuals with alcoholism; however, no previous studies have examined alcohol-associated atrophy using cortical thickness measurements to obtain regional mapping of tissue loss across the full cortical surface. Methods: We compared cortical thickness measures from 31 abstinent individuals with a history of prior alcohol abuse to 34 healthy nonalcoholic control participants (total sample size = 65). Cortical surface models were created from high-resolution T1-weighted images, and cortical thickness was then estimated as the distance between the gray matter / white matter boundary and the outer cortical surface. Results: Abstinent alcoholics showed reduced whole-brain thickness as compared to nonalcoholic participants. Decreases in thickness were found bilaterally in (i) superior frontal, (ii) precentral, (iii) postcentral, (iv) middle frontal, (v) middle / superior temporal, (vi) middle temporal, and (vii) lateral occipital cortical regions. Decreased cortical thickness in the alcoholic group was associated with severity of alcohol abuse. Conclusions: These findings demonstrate widespread reduction in cortical thickness as a consequence of chronic alcoholism, with most severe reductions in frontal and temporal brain regions.

Freeman WM; VanGuilder HD; Guidone E; Krystal JH; Grant KA; Vrana KE. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration. International Journal of Neuropsychopharmacology 14(7): 899-911, 2011. (58 refs.)

Objective. diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption.

Gardini S; Venneri A. Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction. Brain Research Bulletin 87(2-3): 205-211, 2012. (45 refs.)

A number of neuroimaging studies have shown that drug addiction is associated with morphological differences in several brain areas, including orbito-frontal and limbic structures. Most of these studies have investigated patients with addiction to cocaine. The neurobiological mechanisms which play a role in drug addiction are not fully understood, however, and the causal factors remain under investigation. The present study investigated morphological differences between patients with history of cocaine (N=14) and heroin (N=24) abuse and healthy matched controls (N=24). A 3D T1W MRI scan was acquired for all participants and the grey matter images of each patient group compared with those of controls. A direct comparison of the two addiction groups was also carried out. When compared with controls cocaine dependent patients had lower grey matter values in the left middle occipital gyrus, right putamen and insula, whereas heroin abusers had lower grey matter values in the right insula. The direct comparison between the two addiction groups showed that cocaine abusers had less grey matter in the right posterior cingulate, medio-temporal and cerebellar regions, whereas heroin abusers showed less grey matter in parietal regions on both sides, including postcentral gyrus and inferior parietal lobule. Reduced right posterior insular cortex was commonly found in both cocaine and heroin dependent patients. This morphological difference might represent a structural marker of addiction, which is independent of the discrete regional effects of each psychotropic substance of abuse, and might constitute a possible neurobiological vulnerability or diathesis to addiction. Equally, the discrete structural differences emerging from the direct comparison of cocaine and heroin abusers might reflect the effects of differential drug binding in the brain and/or express a form of neurobiological vulnerability which might explain individual drug choice.

Gonzalez-Reimers E; Fernandez-Rodriguez CM; Santolaria-Fernandez F; de la Vega-Prieto MJ; Martin-Gonzalez C; Gomez-Rodriguez MA et al. Interleukin-15 and other myokines in chronic alcoholics. Alcohol and Alcoholism 46(5): 529-533, 2011. (24 refs.)

Aims: Interleukin (IL)-15 is highly expressed in skeletal muscle, where it exerts anabolic effects, increasing protein content in muscle fibres and promoting muscle growth. Alcoholics frequently suffer myopathy. Therefore, we analyse the behaviour of IL-15 (and other myokines, such as IL-6, IL-8 and tumour necrosis factor alpha (TNF-alpha)) in alcoholics. Methods: These myokines and also malondialdehyde (MDA)-a lipid peroxidation product-were determined by radioimmunoanalytic techniques in blood samples of 35 chronic alcoholics and 13 age- and sex-matched controls, and compared with body composition, nutritional status, liver function, amount of ethanol and routine biochemical variables. Results: IL-15, IL-6, TNF-alpha, IL-8 and MDA were all higher in alcoholics than in controls; MDA and IL-6 were clearly related with liver function impairment and short-term prognosis, whereas IL-15 was higher among those who died and was related to serum bilirubin. No relation was found between IL-15 and lean mass. Conclusion: IL-15 levels were higher in alcoholics than in controls, especially among those who died within 18 months after admission. They are not related with muscle mass, intensity of alcoholism or nutritional status, but only with serum bilirubin. IL-6 showed inverse correlations with liver function, intensity of alcoholism, nutritional status, left arm muscle mass and short-term mortality.

Gustavsson A; Svensson M; Jacobi F; Allgulander C; Alonso J; Beghi E et al. Cost of disorders of the brain in Europe 2010. European Neuropsychopharmacology 21(10): 718-779, 2011. (434 refs.)

Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of 386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. Results: The total cost of disorders of the brain was estimated at (sic)798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between (sic)285 for headache and (sic)30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was (sic)1550 on average but varied by country. The cost (in billion (sic)PPP 2010) of the disorders of the brain included in this study was as follows: addiction: (sic)65.7; anxiety disorders: (sic)74.4; brain tumor: (sic)5.2; child/adolescent disorders: (sic)21.3; dementia: (sic)105.2; eating disorders: (sic)0.8; epilepsy: (sic)13.8; headache: (sic)43.5; mental retardation: (sic)43.3; mood disorders: (sic)113.4; multiple sclerosis: (sic)14.6; neuromuscular disorders: (sic)7.7; Parkinson's disease: (sic)13.9; personality disorders: (sic)27.3; psychotic disorders: (sic)93.9; sleep disorders: (sic)35.4; somatoform disorder: (sic)21.2; stroke: (sic)64.1; traumatic brain injury: (sic)33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted (sic)477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

Hakenewerth AM; Millikan RC; Rusyn I; Herring AH; North KE; Barnholtz-Sloan JS et al. Joint Effects of Alcohol Consumption and Polymorphisms in Alcohol and Oxidative stress metabolism genes on risk of head and neck cancer. Cancer Epidemiology, Biomarkers & Prevention 20(11): 2438-2449, 2011. (38 refs.)

Background: Single-nucleotide polymorphisms (SNP) in alcohol metabolism genes are associated with squamous cell carcinoma of the head and neck (SCCHN) and may influence cancer risk in conjunction with alcohol. Genetic variation in the oxidative stress pathway may impact the carcinogenic effect of reactive oxygen species produced by ethanol metabolism. We hypothesized that alcohol interacts with these pathways to affect SCCHN incidence. Methods: Interview and genotyping data for 64 SNPs were obtained from 2,552 European-and African-American subjects (1,227 cases and 1,325 controls) from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study of SCCHN conducted in North Carolina from 2002 to 2006. We estimated ORs and 95% confidence intervals (CI) for SNPs and haplotypes, adjusting for age, sex, race, and duration of cigarette smoking. P values were adjusted for multiple testing using Bonferroni correction. Results: Two SNPs were associated with SCCHN risk: ADH1B rs1229984Aallele (OR = 0.7; 95% CI, 0.6-0.9) and ALDH2 rs2238151 C allele (OR = 1.2; 95% CI, 1.1-1.4). Three were associated with subsite tumors: ADH1B rs17028834 C allele (larynx, OR = 1.5; 95% CI, 1.1-2.0), SOD2 rs4342445 A allele (oral cavity, OR = 1.3; 95% CI, 1.1-1.6), and SOD2 rs5746134 T allele (hypopharynx, OR = 2.1; 95% CI, 1.2-3.7). Four SNPs in alcohol metabolism genes interacted additively with alcohol consumption: ALDH2 rs2238151, ADH1B rs1159918, ADH7 rs1154460, and CYP2E1 rs2249695. No alcohol interactions were found for oxidative stress SNPs. Conclusions and Impact: Previously unreported associations of SNPs in ALDH2, CYP2E1, GPX2, SOD1, and SOD2 with SCCHN and subsite tumors provide evidence that alterations in alcohol and oxidative stress pathways influence SCCHN carcinogenesis and warrant further investigation.

Hanson KL; Medina KL; Padula CB; Tapert SF; Brown SA. Impact of adolescent alcohol and drug use on neuropsychological functioning in young adulthood: 10-year outcomes. Journal of Child & Adolescent Substance Abuse 20(2): 135-154, 2011. (52 refs.)

Because of ongoing neuromaturation, youth with chronic alcohol/substance use disorders (AUD/SUD) are at risk for cognitive decrements during young adulthood. We prospectively examined cognition over 10 years based on AUD/SUD history. Youth (N=51) with no AUD/SUD history (n=14), persisting AUD/SUD (n=18), or remitted AUD/SUD (n=19) were followed over 10 years with neuropsychological assessments. Groups were compared at baseline and 10-year follow-up. Both AUD/SUD groups declined in visuospatial construction at year 10 (p=.001). Further, cumulative alcohol use (p.01) and drug withdrawal (p.05) predicted year-10 visuospatial function. Alcohol use predicted verbal learning/memory (p.05), while stimulant use predicted visual learning/memory (p=.01). More recent substance use predicted poorer executive function (p.05). In conclusion, heavy alcohol and other substance use from adolescence through young adulthood may produce cognitive disadvantages, including visuospatial and memory decline. Youth with heavy, chronic alcohol use and/or drug withdrawal symptoms may be at particular risk.

Houben K; Wiers RW; Jansen A. Getting a grip on drinking behavior: Training working memory to reduce alcohol abuse. Psychological Science 22(7): 968-975, 2011. (36 refs.)

Alcohol abuse disrupts core executive functions, including working memory (WM)-the ability to maintain and manipulate goal-relevant information. When executive functions like WM are weakened, drinking behavior gets out of control and is guided more strongly by automatic impulses. This study investigated whether training WM restores control over drinking behavior. Forty-eight problem drinkers performed WM training tasks or control tasks during 25 sessions over at least 25 days. Before and after training, we measured WM and drinking behavior. Training WM improved WM and reduced alcohol intake for more than 1 month after the training. Further, the indirect effect of training on alcohol use through improved WM was moderated by participants' levels of automatic impulses: Increased WM reduced alcohol consumption in participants with relatively strong automatic preferences for alcohol. These findings are consistent with the theoretical framework and demonstrate that training WM may be an effective strategy to reduce alcohol use by increasing control over automatic impulses to drink alcohol.

Howe M; Leidal A; Montgomery D; Jackson E. Role of cigarette smoking and gender in acute coronary syndrome events. American Journal of Cardiology 108(10): 1382-1386, 2011. (17 refs.)

Cigarette smoking has been associated with lower mortality after an acute coronary event. We hypothesized that the improved survival in smokers is related to demographic differences and sought to further evaluate the gender disparities in smokers after an acute coronary event. A prospective cohort of 3,588 patients hospitalized at a single center from 1999 to 2006 was identified. Smoking status, in-hospital and 6-month follow-up death, and cardiovascular events (i.e., myocardial infarction, stroke, cardiac-related rehospitalization, and unscheduled revascularization) were assessed. The prevalence of smoking in men increased over time. The smokers were younger at presentation with fewer co-morbidities than nonsmokers. Male smokers had lower mortality (3.2% vs 5.4%, p = 0.04) and fewer cardiovascular events (33.1% vs 42.4%, p = 0.003) at 6 months than nonsmokers. However, after adjusting for age and co-morbidities, smoking was not an independent predictor of events (odds ratio 0.88, 95% confidence interval 0.67 to 1.17). Female smokers had mortality (5.6% vs 8.4%, p = 0.15) and cardiovascular events (54.5% vs 49.7%, p = 0.28) at 6 months similar to that of nonsmokers, with a nonsignificant trend toward increased risk after adjustment (odds ratio 1.31, 95% confidence interval 0.90 to 1.93). Among smokers, female gender remained a significant risk factor for cardiovascular events at 6 months (odds ratio 2.35, 95% confidence interval 1.58 to 3.50), even after adjustment for age and co-morbidities. In conclusion, smokers experienced acute coronary event events earlier than did nonsmokers. Younger age and fewer co-morbidities likely account for most observed survival benefit in smokers, although female smokers are more likely to experience cardiovascular complications by 6 months than male smokers.

Kelly DL; Myers CS; Abrams MT; Feldman S; Park J; McMahon RP et al. The impact of substance abuse on osteoporosis screening and risk of osteoporosis in women with psychotic disorders. Osteoporosis International 22(4): 1133-1143, 2011. (48 refs.)

Review of the 1-year prevalence of screening for osteoporosis and of osteoporosis or idiopathic fracture in Maryland Medicaid administrative records found that screening rates did not differ among women in the control population, women with psychosis, and women with major mood disorders, but were reduced compared to controls in women with substance use disorder, with or without psychosis. Prevalence of osteoporosis was increased compared to controls in women with major mood disorders or women over 55 dually diagnosed with psychosis and substance use disorder. Osteoporosis is a major public health concern. Substance abuse and psychosis may be risk factors, however, frequency of screening and disease risk in women with psychotic disorders and substance use disorder (SUD) remains unknown. This study examined rates (FY 2005) of osteoporosis screening and disease risk in Medicaid enrolled women aged 50 to 64 (N = 18,953). Four diagnostic groups were characterized: (1) psychosis, (2) SUD, (3) major mood disorder, and (4) controls. The interaction of psychosis and SUD on screening and disease prevalence of osteoporosis was tested. The prevalence of osteoporosis across the entire population was 6.7%. Four percent of those without an osteoporosis diagnosis received osteoporosis screening with no notable differences between psychosis and controls. Those with SUD, however, had a significant reduction in screening compared to controls (OR = 0.61, 95% CI = 0.40-0.91, p = 0.016). Women with a major mood disorder were more likely to have osteoporosis in their administrative record (OR = 1.32, 95% CI = 1.03-1.70, p = 0.028) compared to controls. Those who were dually diagnosed (SUD and psychosis) in the oldest ages (55-64 years) had a markedly higher prevalence of osteoporosis compared to controls (OR = 6.4 CI = 1.51-27.6, p = 0.012), whereas this interaction (SUD and psychosis) was not significant in the entire population over age 49. Osteoporosis screening in the Medicaid population is significantly lower for women with SUD, after adjusting for age, race, and Medicaid enrollment category. The prevalence of osteoporosis appears markedly elevated in those with major mood disorders and those over age 55 dually diagnosed with schizophrenia and SUD.

Kerr WC; Karriker-Jaffe K; Subbaraman M; Ye Y. Per capita alcohol consumption and ischemic heart disease mortality in a panel of US states from 1950 to 2002. Addiction 106(2): 313-322, 2011. (41 refs.)

Aims: To estimate the overall impact of alcohol on ischemic heart disease (IHD) mortality in the United States using aggregate-level models and to consider beverage-specific effects that may represent more effectively the changes in drinking patterns over time that are related to both harmful and protective impacts of alcohol consumption on IHD. Design: Several model specifications are estimated, including state-specific autoregressive integrated moving average (ARIMA) models and generalized least squares (GLS) panel models on first-differenced data. Setting: US states from 1950 to 2002. Participants: US general population. Measurements: Per capita alcohol sales and cigarette sales, age-standardized IHD and cirrhosis mortality rates. Findings: Apparent consumption of total alcohol was associated with a significant overall increase of IHD of about 1% mortality per litre of ethanol. Beverage-specific models found that spirits consumption was significantly positively related to IHD mortality overall, for both genders and in three regions defined by drinking culture (or 'wetness'), while beer was found to have a significant protective relationship overall and in the wet region. The results for wine also suggest a protective relationship, but only marginally significant effects were found. Cirrhosis mortality rates were consistently positively related to IHD mortality. Combined results from state-specific ARIMA models including both cigarette sales and cirrhosis rates were generally consistent with the GLS results. Conclusions: Population-level models confirm individual-level findings of both harmful and protective relationships between alcohol use patterns and ischemic heart disease mortality. However, an overall harmful impact of per capita alcohol consumption on IHD mortality was found.

Kerr WC; Subbaraman M; Ye Y. Per capita alcohol consumption and suicide mortality in a panel of US states from 1950 to 2002. Drug and Alcohol Review 30(5, special issue): 473-480, 2011. (41 refs.)

Introduction and Aims. The relationship between per capita alcohol consumption and suicide rates has been found to vary in significance and magnitude across countries. This study utilises a panel of time-series measures from the US states to estimate the effects of changes in current and lagged alcohol sales on suicide mortality risk. Design and Methods. Generalised least squares estimation utilised 53 years of data from 48 US states or state groups to estimate relationships between total and beverage-specific alcohol consumption measures and age-standardised suicide mortality rates in first-differenced semi-logged models. Results. An additional litre of ethanol from total alcohol sales was estimated to increase suicide rates by 2.3% in models utilising a distributed lag specification while no effect was found in models including only current alcohol consumption. A similar result is found for men, while for women both current and distributed lag measures were found to be significantly related to suicide rates with an effect of approximately 3.2% per litre from current and 5.8% per litre from the lagged measure. Beverage-specific models indicate that spirits is most closely linked with suicide risk for women while beer and wine are for men. Unemployment rates are consistently positively related to suicide rates. Discussion and Conclusions. Results suggest that chronic effects, potentially related to alcohol abuse and dependence, are the main source of alcohol's impact on suicide rates in the USA for men and are responsible for about half of the effect for women.

Konrad A; Vucurevic G; Lorscheider M; Bernow N; Thummel M; Chai C et al. Broad disruption of brain white matter microstructure and relationship with neuropsychological performance in male patients with severe alcohol dependence. Alcohol and Alcoholism 47(2): 118-126, 2012. (65 refs.)

In the last years, refined magnetic resonance diffusion tensor imaging (DTI) methods have become available to study microstructural alterations in the human brain. We investigated to what extent white matter tissue abnormalities are present in male patients after chronic, excessive alcohol consumption and if these alterations are correlated with measures of alcohol consumption and neuropsychological performance. Twenty-four detoxified adult male patients with severe alcohol dependence and 23 healthy male control subjects were included in the study. Neuropsychological tests were assessed for executive function, attention, memory and visuospatial function. DTI was acquired and preprocessing of the data was performed using tract-based spatial statistics. Group differences of fractional anisotropy (FA) as well as correlation analyses with neuropsychological measures and drinking history were calculated. Performance in alcoholic patients was significantly poorer in tests of non-verbal reasoning and attention. In detoxified alcoholic patients, lower FA was primarily found in the body of the corpus callosum, but these findings did not correlate directly with behavioral measures. However, executive and psychomotor performance (Trail-Making Test) correlated significantly with FA in right anterior cingulate and left motor areas. These findings provide further evidence for reduced integrity of interhemispheric connections in male patients with severe alcohol dependence, and neurocognitive performance was in part correlated with FA.

Koskinen SM; Ahveninen J; Kujala T; Kaprio J; O'Donnell BF; Osipova D et al. A longitudinal twin study of effects of adolescent alcohol abuse on the neurophysiology of attention and orienting. Alcoholism: Clinical and Experimental Research 35(7): 1339-1350, 2011. (66 refs.)

Background: Long-term functional brain effects of adolescent alcohol abuse remain uncertain, partially because of difficulties in distinguishing inherited deficits from neuronal effects of ethanol and by confounds associated with alcohol abuse, especially nicotine exposure. We conducted a longitudinal twin study to determine neurocognitive effects of adolescent alcohol abuse, as measured with the auditory event-related potential (ERP) component P3, a putative marker of genetic vulnerability to alcoholism. Methods: Twin pairs (N = 177; 150 selected for intrapair concordance/discordance for alcohol-related problems at age 18 1/2) were recruited from ongoing studies of twins born 1975-1979 in Finland. Alcohol and tobacco use were assessed with questionnaires at ages 16, 17, 18 1/2, and similar to 25, and by a structured psychiatric interview concurrent with the ERP testing at mean age 25.8. During ERP recordings, subjects were instructed to detect target tones within a train of frequent "standards" and to ignore occasional "novel" sounds. To distinguish familial factors from ethanol effects, ERP and self-reported alcohol use measures were incorporated into hierarchical multiple regression (HMR) analysis, and intrapair differences in ERP were associated with intrapair differences in alcohol variables. Results: Novel-sound P3 amplitude correlated negatively with self-reported alcohol use in both between- and within-family analyses. No similar effect was observed for target-tone P3. HMR results suggest that twins' similarity for novel-sound P3 amplitude is modulated by their alcohol use, and this effect of alcohol use is influenced by genetic factors. Conclusions: Our results, from a large sample of twins selected from a population-based registry for pairwise concordance/discordance for alcohol problems at 18 1/2, demonstrate that adolescent alcohol abuse is associated with subtle neurophysiological changes in attention and orienting. The changes are reflected in decreased novel-sound P3 amplitude and may be modified by genetic factors.

Levin J. Alcoholism. (Chapter 12). IN: Brizer D; Castandea R, eds. Clinical Addiction Psychiatry. New York: Cambridge University Press, 2011

This book is described as an anthology of essays setting forth the most current and authoritative information on addiction theory, practice and research. Each chapter is authored by a recognized authority in the field. The volume covers diverse material, from the environment, to genetics, culture and spirituality, treatment and pharmacology. The book, with 24 essays, is organized in three parts. This chapter is part of Part II, a section with the title "The Real World." The chapters in this section focus on particular drugs. This chapter deals with alcohol/alcoholism. Other chapters in this section deal with alcohol's presentation and treatment in primary care; nicotine addiction and smoking cessation; clinical approaches in working with cocaine and methadone dependence; methadone maintenance for opiate dependence; and prescription drug abuse.

Liang C; Chen J; Gu W; Wang H; Xue Z. Chronic alcoholism increases the induction dose of propofol. Acta Anaesthesiologica Scandinavica 55(9): 1113-1117, 2011. (16 refs.)

Background: The present study was designed to investigate the possible effect of chronic alcohol intake on propofol and remifentanil requirements, which was determined by quantifying the 50% (EC(50)) and 95% (EC(95)) effective effect-site concentrations for propofol and remifentanil at loss of consciousness (LOC) and after a painful stimulus. Methods: Thirty male patients (alcoholic group; n = 30) with chronic alcoholism and 30 patients (control group; n = 30) with a history of small alcohol intake were anaesthetized with propofol and remifentanil by target-controlled infusion. The predicted drug concentrations and Bispectral Index (BIS) values were recorded at LOC and after no response to painful stimuli. Results: The EC50 and EC95 of propofol at LOC in alcoholic group were 3.15 [95% confidence interval (CI), 2.77-3.37] and 4.05 (95% CI, 3.18-5.26) mg/ml, respectively, and those of the control group were 2.21 (95% CI, 1.92-2.86) and 3.04 (95% CI, 2.45-4.64) mg/ml, respectively. The EC50 and EC95 of remifentanil measured after no response to painful stimuli in the alcoholic group were 3.02 (95% CI, 2.70-3.38) and 4.98 (95% CI, 4.56-5.89) ng/ml, respectively, and those of the control group were 2.95 (95% CI, 2.68-3.33) and 4.86 (95% CI, 4.55-5.92) ng/ml, respectively. The EC50 and EC95 values of propofol at LOC in the control group were significantly lower than that of the alcoholic group. Conclusions: These findings suggest that the induction dose requirements of propofol are increased in alcoholic patients anaesthetized with propofol and remifentanil administered by target controlled infusion.

Lipkin M; Lee J. Alcoholism in primary care. (Chapter 13). IN: Brizer D; Castandea R, eds. Clinical Addiction Psychiatry. New York: Cambridge University Press, 2011

This book is described as an anthology of essays setting forth the most current and authoritative information on addiction theory, practice and research. Each chapter is authored by a recognized authority in the field. The volume covers diverse material, from the environment, to genetics, culture and spirituality, treatment and pharmacology. The book, with 24 essays, is organized in three parts. This chapter is part of Part II, a section with the title "The Real World." The chapters in this section focus on particular drugs. This chapter deals with alcohol/alcoholism and its presentation and clinical care in primary care.. Other chapters in this section deal with twelve step approaches; nicotine addiction and smoking cessation; clinical approaches in working with cocaine and methadone dependence; methadone maintenance for opiate dependence; and prescription drug abuse.

Louis G; Megarbane B; Lavoue S; Lassalle V; Argaud L; Poussel JF et al. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis. Critical Care Medicine 40(3): 970-972, 2012. (8 refs.)

Objective: Very few data are available for critically ill patients with central or extrapontine myelinolysis and according to available evidence, the prognosis seems to be poor. We aimed to describe the baseline characteristics, the management, the long-term prognosis, and the prognostic factors in central or extrapontine myelinolysis. Design: Retrospective observational study considering modified Rankin Scale score >3 or death as an unfavorable outcome. Setting: Forty-six French intensive care units. Patients: Thirty-six patients with central or extrapontine myelinolysis treated in 2000-2010. Interventions: None. Measurements and Main Results: At baseline, 31(86%) patients were alcoholics and 33 (92%) presented with hyponatremia. Mechanical ventilation was required in 32 (89%) patients. At 1-yr follow-up, 11 (31%) patients have died, whereas 14 (56%) survivors have returned to a Rankin score 51. Life-supporting therapies were withheld in 11(31%) patients. Severe cerebral motor disability was the most frequently cited reason. However, five of them were still alive at 1 yr with Rankin score <= 1 for four of them. We found no statistical difference between the 18 (50%) patients with a favorable outcome and the 18 (50%) patients with an unfavorable outcome with regard to severity of illness, suggesting that recovery is possible and unpredictable on the basis of clinical presentation. Chronic alcoholism was less frequent in patients with a favorable outcome as compared with patient with an unfavorable outcome (13 [72%] vs. 18 [100%], p = .04). Conclusions: The prognosis of critically ill patients with central or extrapontine myelinolysis is better than thus far thought despite initial severe clinical manifestations. Regarding the high rate of decisions to withhold life-supporting therapies, the probability of a favorable outcome might be underestimated by intensivists.

MacKay RK; Colson NJ; Dodd PR; Lewohl JM. Differential expression of 14-3-3 isoforms in human alcoholic brain. Alcoholism: Clinical and Experimental Research 35(6): 1041- 1049, 2011. (38 refs.)

Background: Neuropathological damage as a result of chronic alcohol abuse often results in the impairment of cognitive function. The damage is particularly marked in the frontal cortex. The 14-3-3 protein family consists of 7 proteins, beta, gamma, epsilon, zeta, eta, theta, and sigma, encoded by 7 distinct genes. They are highly conserved molecular chaperones with roles in the regulation of metabolism, signal transduction, cell-cycle control, protein trafficking, and apoptosis. They may also play an important role in neurodegeneration in chronic alcoholism. Methods: We used real-time PCR to measure the expression of 14-3-3 mRNA transcripts in both the dorsolateral prefrontal cortex and motor cortex of human brains obtained at autopsy. Results: We found significantly lower 14-3-3 beta, gamma, and theta expression in both cortical areas of alcoholics, but no difference in 14-3-3 eta expression, and higher expression of 14-3-3 sigma in both areas. Levels of 14-3-3 zeta and epsilon transcripts were significantly lower only in alcoholic motor cortex. Conclusions: Altered 14-3-3 expression could contribute to synaptic dysfunction and altered neurotransmission in chronic alcohol misuse by human subjects.

Maurage P; Callot C; Chang B; Philippot P; Rombaux P; de Timary P. Olfactory impairment is correlated with confabulation in alcoholism: Towards a multimodal testing of orbitofrontal cortex. PLoS ONE 6(8): e23190, 2011. (72 refs.)

Background: Olfactory abilities are now a flourishing field in psychiatry research. As the orbitofrontal cortex appears to be simultaneously implicated in odour processing and executive impairments, it has been proposed that olfaction could constitute a cognitive marker of psychiatric states. While this assumption appears promising, very few studies have been conducted on this topic among psychopathological populations. The present study thus aimed at exploring the links between olfaction and executive functions. These links were evaluated using two tasks of comparable difficulty, one known to rely on orbitofrontal cortex processing (i.e., a confabulation task), and one not associated with this area (i.e., Stop-Signal task). Methodology/Principal Findings: Twenty recently detoxified alcoholic individuals and twenty paired controls took part in an experiment evaluating olfactory abilities and executive functioning (i.e., Stop-Signal task and confabulation task). Comorbidities and potential biasing variables were also controlled for. Alcoholic individuals exhibited impaired performance for high-level olfactory processing and significant confabulation problems as compared to controls (but no deficit in Stop-Signal task), even when the influence of comorbidities was taken into account. Most importantly, olfactory abilities and confabulation rates were significantly correlated in both groups. Conclusions/Significance: Alcoholism jointly leads to olfactory and memory source impairments, and these two categories of deficits are associated. These results strongly support the proposition that olfactory and confabulation measures both index orbitofrontal functioning, and suggest that olfaction could become a reliable cognitive marker in psychiatric disorders. Moreover, it underlines the need to take into account these olfactory and source memory impairments in a clinical context.

McCool BA. Ethanol modulation of synaptic plasticity. (review). Neuropharmacology 61(7, special issue): 1097-1108, 2011. (189 refs.)

Synaptic plasticity in the most general terms represents the flexibility of neurotransmission in response to neuronal activity. Synaptic plasticity is essential both for the moment-by-moment modulation of neural activity in response to dynamic environmental cues and for long-term learning and memory formation. These temporal characteristics are served by an array of pre- and post-synaptic mechanisms that are frequently modulated by ethanol exposure. This modulation likely makes significant contributions to both alcohol abuse and dependence. In this review. I discuss the modulation of both short-term and long-term synaptic plasticity in the context of specific ethanol-sensitive cellular substrates. A general discussion of the available preclinical, animal-model based neurophysiology literature provides a comparison between results from in vitro and in vivo studies. Finally, in the context of alcohol abuse and dependence, the review proposes potential behavioral contributions by ethanol modulation of plasticity.

Neafsey EJ; Collins MA. Moderate alcohol consumption and cognitive risk. (review). Neuropsychiatric Disease and Treatment 7: 465-484, 2011. (204 refs.)

We reviewed 143 papers that described the relationship between moderate drinking of alcohol and some aspect of cognition. Two types of papers were found: (1) those that provided ratios of risk between drinkers and nondrinkers (74 papers in total) and (2) those that, although they did not provide such ratios, allowed cognition in drinkers to be rated as "better," "no different," or "worse" than cognition in nondrinkers (69 papers in total). The history of research on moderate drinking and cognition can be divided into two eras: 1977-1997 and 1998-present. Phase I (1977-1997) was the era of neuropsychological evaluation involving mostly young to middle-aged (18-50 years old) subjects. Although initial studies indicated moderate drinking impaired cognition, many later studies failed to confirm this, instead finding no difference in cognition between drinkers and nondrinkers. Phase II (1998-present) was and is the era of mental status exam evaluation involving mostly older (>= 55 years old) subjects. These studies overwhelmingly found that moderate drinking either reduced or had no effect on the risk of dementia or cognitive impairment. When all the ratios of risk from all the studies in phase II providing such ratios are entered into a comprehensive meta-analysis, the average ratio of risk for cognitive risk (dementia or cognitive impairment/decline) associated with moderate "social" (not alcoholic) drinking of alcohol is 0.77, with nondrinkers as the reference group. The benefit of moderate drinking applied to all forms of dementia (dementia unspecified, Alzheimer's disease, and vascular dementia) and to cognitive impairment (low test scores), but no significant benefit against cognitive decline (rate of decline in test scores) was found. Both light and moderate drinking provided a similar benefit, but heavy drinking was associated with nonsignificantly higher cognitive risk for dementia and cognitive impairment. Although the meta-analysis also indicated that wine was better than beer or spirits, this was based on a relatively small number of studies because most studies did not distinguish among these different types of alcohol. Furthermore, a number of the studies that did make the distinction reported no difference among the effects of these different types of alcohol. Therefore, at present this question remains unanswered. Analysis also showed that the presence of the apolipoprotein E epsilon 4 allele eliminated the benefit of moderate drinking. However, this was based on a relatively small number of studies and several other studies have found a beneficial effect of the epsilon e4 allele. Further studies are necessary to settle this question. The benefit of moderate alcohol for cognition was seen in both men and women, although the amount and pattern of drinking is very different between the two sexes. Lastly, the finding of unaffected or significantly reduced cognitive risk in light to moderate drinkers was seen in 14/19 countries for which country-specific ratio data were available, with three of the five remaining countries showing nonsignificant reductions as well. Overall, light to moderate drinking does not appear to impair cognition in younger subjects and actually seems to reduce the risk of dementia and cognitive decline in older subjects.

Oscar-Berman M; Song J. Brain volumetric measures in alcoholics: A comparison of two segmentation methods. Neuropsychiatric Disease and Treatment 7: 75, 2011. (36 refs.)

Measures of regional brain volumes, which can be derived from magnetic resonance imaging (MRI) images by dividing a brain into its constituent parts, can be used as structural indicators of many different neuroanatomical diseases and disorders, including alcoholism. Reducing the time and cost required for brain segmentation would greatly facilitate both clinical and research endeavors. In the present study, we compared two segmentation methods to measure brain volumes in alcoholic and nonalcoholic control subjects: 1) an automated system (FreeSurfer) and 2) a semi-automated, supervised system (Cardviews, developed by the Center for Morphometric Analysis [CMA] at Massachusetts General Hospital), which requires extensive staff and oversight. The participants included 32 abstinent alcoholics (19 women) and 37 demographically matched, nonalcoholic controls (17 women). Brain scans were acquired in a 3 Tesla MRI scanner. The FreeSurfer and CMA methods showed good agreement for the lateral ventricles, cerebral white matter, caudate, and thalamus. In general, the larger the brain structure, the closer the agreement between the methods, except for the cerebral cortex, which showed large between-method differences. However, several other discrepancies existed between the FreeSurfer and CMA volume measures of alcoholics' brains. The CMA volumes, but not FreeSurfer, demonstrated that the thalamus, caudate, and putamen were significantly smaller in male alcoholics as compared with male controls. Additionally, the hippocampus was significantly smaller in alcoholic women compared with women controls. In general, correlation between methods was lowest in male alcoholic subjects, who also showed the greatest abnormalities. These results suggest that although many brain structures can be segmented reliably by CMA and FreeSurfer, low correlations between methods in some regions may be due to morphological changes in the brains of alcoholics.

Parrott AC; Murphy P; Scholey AB. Applied human psychopharmacology: The practical psychobiological consequences of some novel and ancient psychoactive drugs. (editorial). Human Psychopharmacology: Clinical and Experimental 27(2): 103-105, 2012. (37 refs.)

This special applied issue of Human Psychopharmacology is based on two symposia from the 27th International Congress of Applied Psychology (ICAP). This was held at the International Congress Centre, Melbourne, Australia, on July 2010. The first of our two symposia was entitled 'Psychoactive drugs, psychobiological health and wellbeing'. Here, the presenters covered the effects of a range of drugs, including cannabis, alcohol, nicotine, cocaine, ginseng and others. The second symposium was entitled 'Ecstasy-MDMA: psychological and health related implications'; hence, the articles on Ecstasy/MDMA and related recreational stimulant drugs.

Robison AJ; Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nature Reviews. Neuroscience 12(11): 623-637, 2011

Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors DeltaFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-kappaB (NF-kappaB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.

Sameti M; Smith S; Patenaude B; Fein G. Subcortical volumes in long-term abstinent alcoholics: Associations with psychiatric comorbidity. (review). Alcoholism: Clinical and Experimental Research 35(6): 1067- 1080, 2011. (120 refs.)

Background: Research in chronic alcoholics on memory, decision-making, learning, stress, and reward circuitry has increasingly highlighted the importance of subcortical brain structures. In addition, epidemiological studies have established the pervasiveness of co-occurring psychiatric diagnoses in alcoholism. Subcortical structures have been implicated in externalizing pathology, including alcohol dependence, and in dysregulated stress and reward circuitry in anxiety and mood disorders and alcohol dependence. Most studies have focused on active or recently detoxified alcoholics, while subcortical structures in long-term abstinent alcoholics (LTAA) have remained relatively uninvestigated. Methods: Structural MRI was used to compare volumes of 8 subcortical structures (lateral ventricles, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens) in 24 female and 28 male LTAA (mean abstinence = 6.3 years, mean age = 46.6 years) and 23 female and 25 male nonalcoholic controls (NAC) (mean age = 45.6 years) to explore relations between subcortical brain volumes and alcohol use measures in LTAA and relations between subcortical volumes and psychiatric diagnoses and symptom counts in LTAA and NAC. Results: We found minimal differences between LTAA and NAC in subcortical volumes. However, in LTAA, but not NAC, volumes of targeted subcortical structures were smaller in individuals with versus without comorbid lifetime or current psychiatric diagnoses, independent of lifetime alcohol consumption. Conclusions: Our finding of minimal differences in subcortical volumes between LTAA and NAC is consistent with LTAA never having had volume deficits in these regions. However, given that imaging studies have frequently reported smaller subcortical volumes in active and recently detoxified alcoholics compared to controls, our results are also consistent with the recovery of subcortical volumes with sustained abstinence. The finding of persistent smaller subcortical volumes in LTAA, but not NAC, with comorbid psychiatric diagnoses, suggests that the smaller volumes are a result of the combined effects of chronic alcohol dependence and psychiatric morbidity and suggests that a comorbid psychiatric disorder (even if not current) interferes with the recovery of subcortical volumes.

Schulte T; Muller-Oehring EM; Sullivan EV; Pfefferbaum A. Disruption of emotion and conflict processing in HIV infection with and without alcoholism comorbidity. Journal of the International Neuropsychological Society 17(3): 537- 550, 2011. (75 refs.)

Alcoholism and HIV-1 infection each affect components of selective attention and cognitive control that may contribute to deficits in emotion processing based on closely interacting fronto-parietal attention and frontal-subcortical emotion systems. Here, we investigated whether patients with alcoholism, HIV-1 infection, or both diseases have greater difficulty than healthy controls in resolving conflict from emotional words with different valences. Accordingly, patients with alcoholism (ALC, n=20), HIV-1 infection (HIV, n=20), ALC+HIV comorbidity (n=22), and controls (CTL, n=16) performed an emotional Stroop Match-to-Sample task, which assessed the contribution of emotion (happy, angry) to cognitive control (Stroop conflict processing). ALC+HIV showed greater Stroop effects than HIV, ALC, or CTL for negative (ANGRY) but not for positive (HAPPY) words, and also when the cue color did not match the Stroop stimulus color; the comorbid group performed similarly to the others when cue and word colors matched. Furthermore, emotionally salient face cues prolonged color-matching responses in all groups. HIV alone, compared with the other three groups, showed disproportionately slowed color-matching time when trials featured angry faces. The enhanced Stroop effects prominent in ALC+HIV suggest difficulty in exercising attentional top-down control on processes that consume attentional capacity, especially when cognitive effort is required to ignore negative emotions.

Schulte T; Muller-Oehring EM; Sullivan EV; Pfefferbaum A. Synchrony of corticostriatal-midbrain activation enables normal inhibitory control and conflict processing in recovering alcoholic men. Biological Psychiatry 71(3): 269-278, 2012. (71 refs.)

Background: Alcohol dependence is associated with inhibitory control deficits, possibly related to abnormalities in frontoparietal cortical and midbrain function and connectivity. Methods: We examined functional connectivity and microstructural fiber integrity between frontoparietal and midbrain structures using a Stroop Match-to-Sample task with functional magnetic resonance imaging and diffusion tensor imaging in 18 alcoholic and 17 control subjects. Manipulation of color cues and response repetition sequences modulated cognitive demands during Stroop conflict. Results: Despite similar lateral frontoparietal activity and functional connectivity in alcoholic and control subjects when processing conflict, control subjects deactivated the posterior cingulate cortex (PCC), whereas alcoholic subjects did not. Posterior cingulum fiber integrity predicted the degree of PCC deactivation in control but not alcoholic subjects. Also, PCC activity was modulated by executive control demands: activated during response switching and deactivated during response repetition. Alcoholics showed the opposite pattern: activation during repetition and deactivation during switching. Here, in alcoholic subjects, greater deviations from the normal PCC activity correlated with higher amounts of lifetime alcohol consumption. A functional dissociation of brain network connectivity between the groups further showed that control subjects exhibited greater corticocortical connectivity among middle cingulate, posterior cingulate, and medial prefrontal cortices than alcoholic subjects. In contrast, alcoholic subjects exhibited greater midbrain-orbitofrontal cortical network connectivity than control subjects. Degree of microstructural fiber integrity predicted robustness of functional connectivity. Conclusions: Thus, even subtle compromise of microstructural connectivity in alcoholism can influence modulation of functional connectivity and underlie alcohol-related cognitive impairment.

Sellal F. Leo Schnug: Alcoholic dementia as an unexpected source of inspiration for an artist. European Neurology 66(4): 190-194, 2011. (10 refs.)

Artistic creativity can be defined as the ability to challenge established academic representations or tastes, and to produce both innovative and esthetic works. Here, we investigate the influence of alcoholic dementia on creativity by describing the case of the famous painter Leo Schnug. It is clear that Schnug's motor and psychic disorders had a dramatic influence on his late artistic output. His hallucinations, panic attacks and delusions had an influence on both the themes and the personal, expressionistic and easily recognizable style of his work. It is unlikely that he would have attained these had he been in good health.

Sidhpura N; Parsons LH. Endocannabinoid-mediated synaptic plasticity and addiction-related behavior. (review). Neuropharmacology 61(7, special issue): 1070-1087, 2011. (403 refs.)

Endogenous cannabinoids (eCBs) are retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CBI receptors. Substantial evidence indicates that eCBs mediate various forms of short- and long-term plasticity in brain regions involved in the etiology of addiction. The present review provides an overview of the mechanisms through which eCBs mediate various forms of synaptic plasticity and discusses evidence that eCB-mediated plasticity is disrupted following exposure to a variety of abused substances that differ substantially in pharmacodynamic mechanism including alcohol, psychostimulants and cannabinoids. The possible involvement of dysregulated eCB signaling in maladaptive behaviors that evolve over long-term drug exposure is also discussed, with a particular focus on altered behavioral responses to drug exposure, deficient extinction of drug-related memories, increased drug craving and relapse, heightened stress sensitivity and persistent affective disruption (anxiety and depression).

Skov-Ettrup LS; Eliasen M; Ekholm O; Gronbaek M; Tolstrup JS. Binge drinking, drinking frequency, and risk of ischaemic heart disease: A population-based cohort study. Scandinavian Journal of Public Health 39(8): 880-887, 2011. (26 refs.)

Introduction: Light-to-moderate alcohol drinking is associated with a decreased risk of ischaemic heart disease (IHD). However, drinking heavily and in binges has been suggested to increase IHD risk. This complexity makes the issue of binge drinking within the light-to-moderate alcohol range an important area for further investigation. Methods: This population-based cohort study included 26,786 men and women who participated in the Danish National Cohort Study in 1994, 2000, and 2005. Binge drinking (defined >5 drinks/day) and risk of IHD and all-cause mortality was investigated among light-to-moderate drinkers (defined <= 21 and <= 14 drinks/week for men and women, respectively). In the entire study population, we investigated the association between drinking frequency, separately and combined with total weekly alcohol intake, and risk of IHD and all-cause mortality. Results: 1136 individuals developed IHD during a mean follow up of 6.9 years. Among male light-to-moderate drinkers reporting occasional binge drinking, the hazard ratio (HR) of IHD was 0.81 (95% CI 0.61-1.08) compared to male light-to-moderate drinkers reporting no binge drinking. Corresponding HR for women was 0.97 (95% CI 0.54-1.76). For women drinking 5-6 days/week, the risk of IHD was lower than for women drinking 1-2 days/week (HR 0.54, 95% CI 0.32-0.90). We did not observe any patterns when looking at combinations of total weekly alcohol intake and drinking frequency. Conclusions: Among light-to-moderate alcohol drinkers, binge drinking was not associated with risk of IHD and all-cause mortality. Overall, drinking frequency did not appear to be an important determinant of the risk of IHD and all-cause mortality.

Smith MJ; Wang L; Cronenwett W; Goldman MB; Mamah D; Barch DM et al. Alcohol use disorders contribute to hippocampal and subcortical shape differences in schizophrenia. Schizophrenia Research 131(1-3): 174-183, 2011. (48 refs.)

Background: Alcohol abuse and dependence have been reported to exacerbate the clinical course of schizophrenia. However, the neurobiological basis of this co-morbid interaction is unknown. The aim of this study was to determine the relationship of co-morbid alcohol use disorder (AUD) with brain structure abnormalities in schizophrenia patients. Methods: T1-weighted magnetic resonance images were collected from schizophrenia patients without a history of any substance use disorder (SCZ_0, n = 35), schizophrenia patients with a history of AUD only (SCZ_AUD, n = 16), and a healthy comparison group without a history of any substance use disorder (CON, n = 56). Large-deformation, high-dimensional brain mapping was used to quantify the surface shapes of the hippocampus, thalamus, striatum, and globus pallidus in these subject groups. Analysis of variance was used to test for differences in surface shape measures among the groups. Results: SCZ_AUD demonstrated the greatest severity of shape abnormalities in the hippocampus, thalamus, striatum, and globus pallidus as compared to SCZ_0 and CON. SCZ_AUD demonstrated a combination of exaggerated shape differences in regions where SCZ_0 also showed shape differences, and unique shape differences that were not observed in SCZ_0 or CON. Conclusions: Shape differences in schizophrenia were compounded by a history of co-morbid AUD. Future research is needed to determine whether these differences are simply additive or whether they are due to an interaction between the underlying neurobiology of schizophrenia and alcoholism. The consequences of such shape differences for the clinical course of schizophrenia are not yet understood.

Smith S; Fein G. Persistent but less severe ataxia in long-term versus short-term abstinent alcoholic men and women: A cross-sectional analysis. Alcoholism: Clinical and Experimental Research 35(12): 2184-2192, 2011. (33 refs.)

Background: Disturbed gait and balance are among the most consistent and salient sequelae of chronic alcoholism. Results of small sample longitudinal investigations have provided evidence that partial recovery of gait and balance functions in alcoholics may be achieved with abstinence. However, abstinence durations reported have been limited, and their power and generalizability have suffered from small sample sizes. Methods: In this study, we employed a cross-sectional approach to assess gait and balance functions in short-term (6 to 15 weeks) abstinent alcoholics (STAA; n = 70) and long-term (minimum 18 months, mean = 7.38 years) abstinent alcoholics (LTAA; n = 82). STAA and LTAA did not differ with respect to lifetime alcohol consumption, family drinking density, or years of education. In addition, we examined the effects of gender and alcohol use variables. Results: Our main findings were: (i) persistent disturbed gait and balance in STAA and disturbed standing balance in LTAA; (ii) overall less impaired performance of LTAA compared with STAA on gait and balance measures; and (iii) worse performance of STAA (but not LTAA) women, compared with men, on standing balance without visual control. Conclusions: Our results suggest that alcoholics' gait and balance can continue to recover with long abstinence from alcohol, but that deficits persist, especially in eyes-closed standing balance. In addition, our results are consistent with more severe alcohol-induced ataxia in women than in men but suggest that with extended abstinence, women recover gait and balance function to a level comparable with men.

Solowij N; Jones KA; Rozman ME; Davis SM; Ciarrochi J; Heaven PCL et al. Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology 216(1): 131-144, 2011. (67 refs.)

Rationale. Long-term heavy cannabis use can result in memory impairment. Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis. Objectives and methods. In a cross-sectional and prospective neuropsychological study of 181 adolescents aged 16-20 (mean 18.3 years), we compared performance indices from one of the most widely used measures of learning and memory-the Rey Auditory Verbal Learning Test-between cannabis users (n=52; mean 2.4 years of use, 14 days/month, median abstinence 20.3 h), alcohol users (n=67) and non-user controls (n=62) matched for age, education and premorbid intellectual ability (assessed prospectively), and alcohol consumption for cannabis and alcohol users. Results. Cannabis users performed significantly worse than alcohol users and non-users on all performance indices. They recalled significantly fewer words overall (p<0.001), demonstrating impaired learning (p<0.001), retention (p<0.001) and retrieval (p<0.05) (Cohen's d 0.43-0.84). The degree of impairment was associated with the duration, quantity, frequency and age of onset of cannabis use, but was unrelated to alcohol exposure or other drug use. No gender effects were detected and the findings remained after controlling for premorbid intellectual ability. An earlier age of onset of regular cannabis use was associated with worse memory performance after controlling for extent of exposure to cannabis. Conclusions. Despite relatively brief exposure, adolescent cannabis users relative to their age-matched counterparts demonstrated similar memory deficits to those reported in adult long-term heavy users. The results indicate that cannabis adversely affects the developing brain and reinforce concerns regarding the impact of early exposure.

Sorg SF; Taylor MJ; Alhassoon OM; Gongvatana A; Theilmann RJ; Frank LR et al. Frontal white matter integrity predictors of adult alcohol treatment outcome. Biological Psychiatry , 2012. (74 refs.)

Background: Previous research has associated abnormalities in frontal lobe functioning with alcohol relapse. In this study, we used diffusion tensor imaging to investigate whether frontal white matter integrity measured at the start of treatment differs between persons with alcohol use disorders (AUD) who sustain treatment gains and those who return to heavy use after treatment. Methods: Forty-five treatment-seeking AUD inpatients and 30 healthy control subjects were included in the study. Six months after completing treatment, 16 of the AUD participants had resumed heavy use (RHU) and 29 others remained abstinent or drank minimally (treatment sustainers [TS]). Voxel-wise group comparisons (TS vs. RHU) were performed on fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity maps generated from each subject's diffusion tensor imaging scan at the start of treatment. Results: We found significantly lower FA and significantly higher RD in the frontal lobes of the RHU group, relative to the TS group. The RHU group data are consistent with previous reports of abnormal frontal white matter tract abnormalities in persons with AUD. Conclusions: It is possible that the lower FA and higher RD in the RHU group reflect microstructural injury to frontal circuitries, and these may underlie the reduced cognitive control amid heightened reward sensitivity associated with resumption of heavy drinking.

Thoma R; Mullins P; Ruhl D; Monnig M; Yeo RA; Caprihan A et al. Perturbation of the glutamate-glutamine system in alcohol dependence and remission. Neuropsychopharmacology 36(7): 1359- 1365, 2011. (41 refs.)

As acute ethanol exposure inhibits N-methyl-D-aspartate glutamate (Glu) receptors, sudden withdrawal from chronic alcohol use may lead to an increased activation of these receptors with excitotoxic effects. In the longer term, brain levels of Glu and its metabolites, such as glutamine (Gln), are likely to be chronically altered by alcohol, possibly providing a measure of overall abnormal Glu-Gln cycling. However, few studies have assessed concentrations of these metabolites in clinical populations of individuals with alcohol use disorders. Glu and Gln levels were compared in groups of 17 healthy controls and in 13 participants with alcohol dependence. Within the alcohol-dependent group, seven participants had current alcohol use disorder (AUD), and six had AUD in remission for at least 1 year (AUD-R). Neurometabolite concentrations were measured with proton magnetic resonance spectroscopy (H-1-MRS) in a predominantly gray matter voxel that included the bilateral anterior cingulate gyri. Tissue segmentation provided an assessment of the proportion of gray matter in the H-1-MRS voxel. The Drinker Inventory of Consequences (DrInC) and Form-90 were administered to all participants to quantify alcohol consequences and use. Glu level was lower and Gln level was higher in the AUD and AUD-R groups relative to the control group; creatine, choline, myo-inositol, and total N-acetyl groups, primarily N-acetylaspartate did not differ across groups. These results were not confounded by age, sex, or proportion of gray matter in the H-1-MRS voxel. Neurometabolite concentrations did not differ between AUD and AUD-R groups. Subsequent regressions in the combined clinical group, treating voxel gray matter proportion as a covariate, revealed that total score on the DrInC was positively correlated with Gln but negatively correlated with both Glu and gray matter proportion. Regression analyses, including DrInC scores and smoking variables, identified a marginal independent effect of smoking on Gln. The current findings of higher Gln and lower Glu in the combined AUD and AUD-R groups might indicate a perturbation of the Glu-Gln cycle in alcohol use disorders. The absence of differences in mean Glu and Gln between the AUD and AUD-R groups suggests that altered Glu-Gln metabolism may either predate the onset of abuse or persist during prolonged abstinence.

Wang S; Hou XJ; Ding SJ; Guan YT; Zhen HM; Tu LH et al. Refractory hypotension in a patient with Wernicke's encephalopathy. Alcohol and Alcoholism 47(1): 48-51, 2012. (13 refs.)

A 57-year-old male patient with gastric carcinoma underwent radical distal gastrectomy type II + Braun anastomosis, and received total parenteral nutrition for 10 days after surgery, followed by small amounts of semi-liquid nutrition for 3 days and liquid nutrition for 2 days. The patient developed refractory hypotension for more than 1 week in the early course of disease, and on Day 15 after surgery presented with characteristic signs of Wernicke's encephalopathy, including diplopia and mental confusion. The hypotension did not improve despite appropriate fluid replacement soon after admission. Treatment with moderate dose of thiamine for 3 months partly relieved ophthalmoplegia and confusion, but not Korsakoff syndrome. This extraordinary presentation with refractory hypotension and the unusual course of the disease encouraged us to present this case.

Weaver M. Medical sequelae of addiction. (Chapter 3). IN: Brizer D; Castandea R, eds. Clinical Addiction Psychiatry. New York: Cambridge University Press, 2011

White HR; Marmorstein NR; Crews FT; Bates ME; Mun EY; Loeber R. Associations between heavy drinking and changes in impulsive behavior among adolescent boys. Alcoholism: Clinical and Experimental Research 35(2): 295-303, 2011. (38 refs.)

Background: Impulsive behavior in humans predicts the onset of drinking during adolescence and alcohol use disorders (AUDs) in adulthood. It is also possible, however, that heavy drinking may increase impulsive behavior by affecting the development of brain areas that support behavioral control or through other associated mechanisms. This study examined whether drinking heavily during adolescence is related to changes in impulsive behavior with a specific focus on how the association differs across individuals, contingent on the developmental course of their impulsiveness. Method: Data came from a sample of boys (N = 503) who were followed annually from approximate age 8 to age 18 and again at approximate age 24/25. Heavy drinking was defined as experiencing a blood alcohol concentration (BAC) level of 0.08% or higher. At each assessment, the parent and child each reported whether the child was impulsive. Results: First, group-based trajectory analysis was used to identify 4 groups differing in the level and slopes of their trajectories of impulsive behavior from age 9 to age 17: low (13.9%), early adolescence-limited (18.7%), moderate (60.8%), and high (6.6%). These trajectory groups differed in their prevalence of any heavy drinking, peak BACs, and rates of alcohol dependence in adolescence and AUD in early adulthood, with the less impulsive groups being lower on these measures than the more impulsive groups. Heavy drinking was then entered into the model as a time-varying covariate; this measure was lagged so that the results represent change in impulsive behavior the year following heavy drinking. Among boys on the moderate trajectory, those who drank heavily were rated as significantly more impulsive the following year compared to those who did not drink heavily. Conclusions: The association between heavy drinking and impulsive behavior may depend on earlier levels of impulsive behavior with those who are moderately impulsive appearing to be at greatest risk for increased impulsive behavior following heavy drinking. Further research is needed to clarify this association.

Wijnia JW; van de Wetering BJM; Zwart E; Nieuwenhuis KGA; Goossensen MA. Evolution of Wernicke-Korsakoff Syndrome in self-neglecting alcoholics: Preliminary results of relation with Wernicke-Delirium and diabetes mellitus. American Journal on Addictions 21(2): 104-110, 2012. (21 refs.)

We present a descriptive, retrospective study of initial symptoms, comorbidity, and alcohol withdrawal in 73 alcoholic patients with subsequent Korsakoff syndrome. In 25/73 (35%) of the patients the classic triad of Wernicke's encephalopathy with ocular symptoms, ataxia and confusion, was found. In at least 6/35 (17%) of the initial deliria (95% confidence interval: 1025%) we observed no other underlying causes, thus excluding other somatic causes, medication, (recent) alcohol withdrawal, or intoxication. We suggest that these deliria may have been representing Wernicke's encephalopathy. A high frequency (15%) of diabetics may reflect a contributing factor of diabetes mellitus in the evolution of the Wernicke-Korsakoff syndrome.

Zahr NM; Kaufman KL; Harper CG. Clinical and pathological features of alcohol-related brain damage. (review). Nature Reviews. Neurology 7(5): 284- 294, 2011. (181 refs.)

One of the sequelae of chronic alcohol abuse is malnutrition. Importantly, a deficiency in thiamine (vitamin B-1) can result in the acute, potentially reversible neurological disorder Wernicke encephalopathy (WE). When WE is recognized, thiamine treatment can elicit a rapid clinical recovery. If WE is left untreated, however, patients can develop Korsakoff syndrome (KS), a severe neurological disorder characterized by anterograde amnesia. Alcohol-related brain damage (ARBD) describes the effects of chronic alcohol consumption on human brain structure and function in the absence of more discrete and well-characterized neurological concomitants of alcoholism such as WE and KS. Through knowledge of both the well-described changes in brain structure and function that are evident in alcohol-related disorders such as WE and KS and the clinical outcomes associated with these changes, researchers have begun to gain a better understanding of ARBD. This Review examines ARBD from the perspective of WE and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions. An awareness of the consequences of chronic alcohol consumption on human behavior and brain structure can enable clinicians to improve detection and treatment of ARBD.

Zanardini R; Fontana A; Pagano R; Mazzaro E; Bergamasco F; Romagnosi G et al. Alterations of brain-derived neurotrophic factor serum levels in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research 35(8): 1529-1533, 2011. (46 refs.)

Background: Alcohol dependence is a chronic relapsing disorder characterized by repetitive alcohol drinking patterns and a loss of control over alcohol consumption. Recent studies have hypothesized that dysregulations in brain neurotrophic support regulated by neurotrophins may be involved in the vulnerability to dependence and in the brain damage caused by chronic alcohol consumption. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a pivotal role in neurodevelopment and in the maintenance of adult brain homeostasis through the regulation of neurogenesis and neuronal plasticity. The role of BDNF and its signaling in the mechanisms of alcohol dependence has been well documented in studies of animal models, but a few studies have been conducted in human peripheral tissues. On the basis of this rationale, we compared BDNF levels in both serum and plasma in alcohol-dependent patients and healthy volunteers. Methods: Thirty-seven patients with a principal diagnosis of alcohol dependence were recruited. In parallel, a control group of 37 unrelated volunteers matched for gender and age was enrolled. Serum and plasma BDNF levels were measured by ELISA. Results: A significant reduction in BDNF serum levels was observed in the patient group compared to healthy subjects (p = 0.028). On the contrary, no difference in BDNF plasma levels was evident between patients and controls. Conclusions: In conclusion, our data show an alteration of BDNF peripheral content in patients with alcohol dependence, suggesting the involvement of this neurotrophin in this psychopathology.