Katrin Charlet

Increased neural activity during high working memory load predicts low relapse risk in alcohol dependence

Working memory (WM) impairments are often observed in alcohol‐dependent individuals, especially in early abstinence, which may contribute to an increased relapse risk after detoxification. Brain imaging studies on visuospatial WM in alcohol‐dependent patients compared to controls indicate that information processing requires compensatory increased neural activation to perform at a normal level. However, to date, no study tested whether such increased neural WM activation patterns or the lack thereof predict relapse behavior in alcohol‐dependent individuals, and whether such differences persist when adequately correcting for individual grey matter differences. We combined analyses of neural activation during an n‐back task and local grey matter volumes using Biological Parametric Mapping in 40 detoxified alcohol‐dependent patients and 40 matched healthy controls (HC), and assessed prospective relapse risk during a 7‐month follow‐up period. Despite equal task performance, we found increased functional activation during high versus low cognitive WM load (2‐back–0‐back) in bilateral rostral prefrontal cortex (BA10) and bilateral ventrolateral prefrontal cortex (BA45,47) in prospective abstainers versus relapsers, and further in left/right lateral/medial premotor cortex (BA6,8) in abstainers versus HC. In prospective abstainers, but not relapsers, subtle cognitive impairment was associated with increased neural task activity in the premotor cortex. These findings suggest that in prospective abstainers, higher functional engagement of presumably less impaired neural resources in executive behavioral control brain areas (BA10, 45, 47, 6, 8) may constitute a resilience factor associated with good treatment outcome.

The Dopamine System in Mediating Alcohol Effects in Humans

Recent brain–imaging studies revealed that the development and maintenance of alcohol dependence is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Dysfunctional reward processing, impaired reinforcement learning and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with personality traits, cognition and emotion processing.

Genetic Variation in the Atrial Natriuretic Peptide Transcription Factor GATA4 Modulates Amygdala Responsiveness in Alcohol Dependence

BACKGROUND Two genome-wide association studies recently showed alcohol dependence to be associated with a single-nucleotide polymorphism (rs13273672) located on a gene (GATA4) that encodes a transcription factor of atrial natriuretic peptide (ANP). A growing body of evidence suggests that ANP might be involved in the symptomology of alcohol dependence. This study examined whether reactivity to alcohol cues in the ANP target region amygdala, a key area implicated in addictive behavior, differs depending on the GATA4 genotype of a patient. We also investigated potential associations between these differences in amygdala activation and relapse behavior. METHODS Eighty-one abstinent, alcohol-dependent patients completed a functional magnetic resonance imaging cue-reactivity task in a 3-Tesla scanner and provided blood samples for DNA extraction. RESULTS The results showed significantly lower alcohol-cue-induced activations in G-allele carriers as compared with AA-homozygotes in the bilateral amygdala. A survival analysis revealed that a stronger alcohol-specific amygdala response predicted a lowered risk for relapse to heavy drinking in the AA-homozygotes, whereas this effect could not be observed in G-allele carriers. CONCLUSIONS These results illuminate potential underlying mechanisms of the involvement of the GATA4 gene in the etiology of alcohol dependence via its influence on ANP and amygdala processing.

Increased mesolimbic cue-reactivity in carriers of the mu-opioid-receptor gene OPRM1 A118G polymorphism predicts drinking outcome: A functional imaging study in alcohol dependent subjects

The endogenous opioid system is involved in the pathophysiology of alcohol-use disorders. Genetic variants of the opioid system alter neural and behavioral responses to alcohol. In particular, a single nucleotide polymorphism rs1799971 (A118G) in the mu-opioid receptor gene (OPRM1) is suggested to modulate alcohol-related phenotypes and neural response in the mesocorticolimbic dopaminergic system. Little is known about the clinical implications of these changes. The current study investigated the relationship of genotype effects on subjective and neural responses to alcohol cues and relapse in a sample of abstinent alcohol-dependent patients. Functional magnetic resonance imaging (fMRI) was used to investigate alcohol cue-reactivity and drinking outcome of 81 abstinent alcohol-dependent patients. G-allele carriers displayed increased fMRI cue-reactivity in the left dorsal striatum and bilateral insulae. Neural responses to alcohol cues in these brain regions correlated positively with subjective craving for alcohol and positive expectations of alcohol׳s effects. Moreover, alcohol cue-reactivity in the left dorsal striatum predicted time to first severe relapse. Current results show that alcohol-dependent G-allele carriers׳ increased cue-reactivity is associated with an increased relapse risk. This suggests that genotype effects on cue-reactivity might link the OPRM1 A118G risk allele with an increased relapse risk that was reported in earlier studies. From a clinical perspective, risk-allele carriers might benefit from treatments, such as neuro-feedback or extinction-based therapy that are suggested to reduce mesolimbic reactivity.

Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielbergers state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

The effects of single nucleotide polymorphisms in glutamatergic neurotransmission genes on neural response to alcohol cues and craving

The aim of the current study was to determine genotype effects of four single nucleotide polymorphisms (SNPs) in the genes of the N‐Methyl‐d‐aspartate receptor (GRIN1, GRIN2A, GRIN2C) and kainate receptor (GRIK1), which have been previously associated with alcoholism, on behavior, neural cue‐reactivity and drinking outcome. Eighty‐six abstinent alcohol dependent patients were recruited from an in‐patient setting. Neuropsychological tests, genotyping and functional magnetic resonance imaging (fMRI) were used to study genotype effects. GRIN2C risk allele carriers displayed increased alcohol cue‐induced activation in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC). Neural activation in the ACC positively correlated with craving for alcohol (r = 0.201, P = 0.032), whereas activation in the dlPFC showed a negative association (r = −0.215, P = 0.023). In addition, dlPFC activation predicted time to first relapse (HR = 2.701, 95%CI 1.244–5.864, P = 0.012). GRIK1 risk allele carriers showed increased cue‐induced activation in the medial prefrontal (PFC) and orbitofrontal cortex (OFC) and in the lateral PFC and OFC. Activation in both clusters positively correlated with alcohol craving (rmedOFC, medPFC = 0.403, P = 0.001, rlatOFC, latPFC = 0.282, P = 0.008), and activation in the cluster that encompassed the medial OFC predicted time to first relapse (HR = 1.911, 95%CI 1.030–3.545, P = 0.040). Findings indicate that SNPs in the GRIN2C and GRIK1 genes are associated with altered cue‐induced brain activation that is related to craving for alcohol and relapse risk.

Harm reduction-a systematic review on effects of alcohol reduction on physical and mental symptoms

Based on the knowledge that alcohol misuse causes a multitude of diseases and increased mortality, this systematic review examines whether a reduction of the individual alcohol consumption can contribute to a minimization of health risks within a harm reduction approach. In fact, the reviewed 63 studies indicate that interventions aiming at alcohol reduction (including total abstinence as one possible therapeutic aim) indeed resulted in or were associated with positive effects in harmful, hazardous or alcohol‐dependent drinkers. Major benefits were observed for reducing alcohol‐associated injuries, recovery of ventricular heart function in alcoholic cardiomyopathy, blood pressure lowering, normalization of biochemical parameter, body weight reduction, histological improvement in pre‐cirrhotic alcohol‐related liver disease and slowed progression of an already existing alcohol‐attributable liver fibrosis. Furthermore, reduced withdrawal symptoms, prevalence of psychiatric episodes and duration of in‐patient hospital days, improvement of anxiety and depression symptoms, self‐confidence, physical and mental quality of life, fewer alcohol‐related adverse consequences as well as lower psychosocial stress levels and better social functioning can result from reduced alcohol intake. The reviewed literature demonstrated remarkable socioeconomic cost benefits in areas such as the medical health‐care system or workforce productivity. Individuals with heightened vulnerability further benefit significantly from alcohol reduction (e.g. hypertension, hepatitis C, psychiatric co‐morbidities, pregnancy, but also among adolescents and young adults). Concluding, the reviewed studies strongly support and emphasize the importance and benefits of early initial screening for problematic alcohol use followed by brief and other interventions in first contact medical health‐care facilities to reduce alcohol intake.

GATA4 variant interaction with brain limbic structure and relapse risk: A voxel-based morphometry study

Atrial natriuretic peptide (ANP) receptors are highly expressed in the amygdala, caudate and hypothalamus. GATA4 gene encodes a transcription factor of ANP associated with the pathophysiology of alcohol dependence. We have previously demonstrated that the GATA4 single nucleotide polymorphism (SNP) rs13273672 revealed stronger alcohol-specific amygdala activation associated with lowered relapse risk to heavy drinking at 90 days in the AA-homozygotes. Our understanding however with respect to GATA4 variation on gray matter (GM) regional amygdala, caudate and hypothalamus volume is limited. We investigated GM differences specific to GATA4 and hypothesized that GM alterations will be predictive of heavy relapse. Eighty-three recently detoxified alcohol dependent patients were included. Neuroimaging data was analyzed using Voxel Based Morphometry (VBM). The main effects of GM volume and genotype as well as their interaction effect on time to heavy relapse (60 and 90 days) were analyzed using cox regression. Significant higher GM volume was found for the AA-genotype group compared with AG/GG-genotype in the hypothalamus and caudate. A significant interaction was revealed between caudate and amygdala GM volume and GATA4 genotype on time to heavy relapse. The interaction was expressed by means of higher GM in the AA genotype group to be associated with reduced risk to relapse whereas in the AG/GG group higher GM was associated with increased risk to relapse. This is the first report on GM regional volume alterations specific to GATA4 genotype [(SNP) rs13273672] and its association with relapse in alcohol dependence. Current findings further support the role of GATA4 in alcoholism.

Public mental health: a call to action

K. Wahlbeck (1) convincingly argues that the prominent role of social factors in wellbeing and mental health is supported by overwhelming evidence. He states that a series of studies have shown how evidence-based programs to prevent mental disorders can be translated into everyday practice. However, he cautions that there is a lack of action in the most affluent countries, while there is an even wider gap between possible ways of intervention and current funding in the less affluent ones. Furthermore, he emphasizes the need for interdisciplinary research to broaden the theory-base of programs aimed at the promotion of public mental health. Let us briefly examine these arguments. There is indeed an abundance of studies showing an association between poverty and social exclusion on the one hand, and poor mental health on the other (2,3). However, correlation is not causation, and it may be argued that variables not detected in these studies – such as unknown familial influences including environmental and (epi-)genetic factors – may explain the observed correlations. But they either cannot be easily targeted (such as unknown familial factors) or are not even amenable to social interventions (such as genetic factors). Against such therapeutic nihilism, two arguments can be raised. First, a series of animal experiments and human studies have shown that social stress factors, particularly exclusion, stigmatization and discrimination, directly impact on the neurobiological correlates of mental disorders, impair cognitive capacities and promote aggression, drug intake and negative mood states (4,5). Indeed, even fluid IQ as a measure of complex cognitive capacities has been associated with variation in dopaminergic neurotransmission, which in turn is strongly affected by stress exposure (6-8). Second, most twin research has relied on the (controversial) assumption that gene-gene interactions are only additive and cannot exponentially increase similarity (e.g., when variation in multiple genes increases neurotransmitter synthesis and at the same time decreases both reuptake and metabolism). On the other hand, the “equal environment” assumption on which most twin studies are based does not differentially capture complex genotype-phenotype interactions. We caution that both supraadditive genetic effects as well as the presence of complex genotype-phenotype interactions could lead to an overestimation of genetic effects, which could in turn override environmental effects in twin study designs that assume only additive interactions (9). Hence, the current absence of evidence for environmental effects in many twin studies is not evidence of absence. Moreover, there is emerging evidence that the effects of genetic variation on behavioral phenotypes are amenable to targeted behavioral interventions, such as cognitive training (10). These considerations call for study designs that look at complex genotype-phenotype interactions and assess not only genetic but also epigenetic effects (11). With respect to Wahlbecks argument that insufficient funds are spent on preventive programs in affluent countries and that there is a wide gap between available funds and social needs in the less affluent ones, one can only but agree and call for direct action. Epidemiological studies suggest that mental disorders impose a huge burden on individuals and their families, which is further augmented by social exclusion and stigmatization (12,13). It may be exactly due to this persisting stigma that, in spite of good evidence for the effectiveness of preventive programs, even rich countries do not provide sufficient funds. For those countries that are less affluent, some tough choices have to be made: it may be less helpful to promote hospital care if there is a lack of social consultation, as we experienced in Afghanistan and Mali, while educating social workers, nurses and general practitioners may have to take priority (14,15). Wahlbeck calls for interdisciplinary research to promote the theory basis of public health. Indeed, we strongly agree and suggest that both quantitative and qualitative research has its place in this respect. While animal experiments, longitudinal studies and epidemiological data can provide a quantitative account of the interaction of social and individual factors contributing to mental health and distress, qualitative studies can generate new lines of research and explore what a given situation really means for patients and their relatives as well as the general population. Indeed, neuroscience has turned social (16) and it is time for epidemiology and social psychiatry to embrace multi-level approaches to mental health and to put viable programs into practice.

Can reduced drinking be a viable goal for alcohol dependent patients

Rachel Jenkins, Caleb Othieno, Linnet Ongeri, Michael Ongecha, Peter Sifuna, Raymond Omollo, Bernhards Ogutu Health Services and Population Research Department, Institute of Psychiatry, King’s College London, London, UK; Department of Psychiatry, University of Nairobi, Nairobi, Kenya; Kenya Medical Research Institute, Nairobi, Kenya; Kenya Medical Research Institute, Kisian, Kisumu, Kenya; Kombewa Health and Demographic Surveillance Site, Kombewa, Kenya 1. Langhorne J, Ndungu FM, Sponaas AM et al. Nat Immunol 2008;9:725-32. 2. Jenkins R, Omollo R, Ongecha M et al. Malar J 2015;14:263. 3. Jenkins R, Othieno C, Ongeri L et al. Int J Environ Res Publ Health 2015;12: 5310-28. 4. Jenkins R, Othieno C, Ongeri L et al. BMC Psychiatry 2015;15:309. 5. Jenkins R, Othieno C, Omollo R et al. Int J Environ Res Publ Health 2015; 12:13494-509. 6. Jenkins R, Othieno C, Ongeri L et al. Glob Ment Health 2015;2:e14. 7. Jenkins R, Othieno C, Omollo R et al. BMC Public Health 2015;15:759. 8. Jenkins R, Othieno C, Ongeri L et al. BMC Psychiatry 2015;15:230. 9. Sifuna P, Oyugi M, Ogutu B et al. Int J Epidemiol 2014;43:1097-104.