Juergen Gallinat

Common biology of craving across legal and illegal drugs – a quantitative meta-analysis of cue-reactivity brain response

The present quantitative meta‐analysis set out to test whether cue‐reactivity responses in humans differ across drugs of abuse and whether these responses constitute the biological basis of drug craving as a core psychopathology of addiction. By means of activation likelihood estimation, we investigated the concurrence of brain regions activated by cue‐induced craving paradigms across studies on nicotine, alcohol and cocaine addicts. Furthermore, we analysed the concurrence of brain regions positively correlated with self‐reported craving in nicotine and alcohol studies. We found direct overlap between nicotine, alcohol and cocaine cue reactivity in the ventral striatum. In addition, regions of close proximity were observed in the anterior cingulate cortex (ACC; nicotine and cocaine) and amygdala (alcohol, nicotine and cocaine). Brain regions of concurrence in drug cue‐reactivity paradigms that overlapped with brain regions of concurrence in self‐reported craving correlations were found in the ACC, ventral striatum and right pallidum (for alcohol). This first quantitative meta‐analysis on drug cue reactivity identifies brain regions underlying nicotine, alcohol and cocaine dependency, i.e. the ventral striatum. The ACC, right pallidum and ventral striatum were related to drug cue reactivity as well as self‐reported craving, suggesting that this set of brain regions constitutes the core circuit of drug craving in nicotine and alcohol addiction.

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

Confirmation of Association Between the Val66Met Polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) Gene and Bipolar I Disorder

Recent studies have indicated that the brain‐derived neurotrophic factor (BDNF) gene is involved in the etiology of bipolar disorder (BPD). Two family‐based association studies showed that the Val allele of the functional polymorphism Val66Met in the BDNF gene is associated with BPD; however, others could not confirm the results. Here we performed a replication study in an independent sample and tested the hypothesis that the Val66 allele in the BDNF gene confers susceptibility to bipolar I disorder (BPI). Six hundred twenty‐one patients with BPI and 998 control subjects were genotyped for the Val66Met polymorphism. All cases and controls were of European descent. All BPI patients had a positive family history of affective disorder. The frequency of the Val allele was significantly increased in BPI patient when compared to controls (χ2 = 4.8; df = 1; P = 0.028; two‐sided; OR = 1.22; 95% CI: 1.02–1.47). Results confirm previous findings and suggest that the Val allele increases risk for BPI in patients of European descent. Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity.

BACKGROUND Brain-derived neurotrophic factor (BDNF) signaling at synapses improves synaptic strengthening associated with learning and memory. In the present study we hypothesized that serum BDNF concentration is associated with in vivo level of cerebral N-acetylaspartate (NAA), a well established marker of neuronal integrity. METHODS In 36 healthy subjects BDNF serum concentration and absolute concentration of NAA together with other metabolites were measured by proton magnetic resonance spectroscopy (1H-MRS) in regions with high BDNF levels (anterior cingulate cortex [ACC], left hippocampus). Relationship between BDNF concentration and brain metabolites was studied in linear regression analysis with BDNF concentration as dependent variable and metabolite concentrations, age, and gender as predictor variables. RESULTS The BDNF serum concentrations were positively associated with the concentrations of NAA (T = 2.193, p = .037) and total choline (T = 1.997, p = .055; trend) but not total creatine or glutamate in the ACC. No significant association was observed between BDNF serum concentration and absolute metabolite concentrations in the hippocampus. CONCLUSIONS The preliminary data might indicate that BDNF serum concentration reflects some aspects of neuronal plasticity as indicated by its association with NAA level in the cerebral cortex. The results would be in line with the notion that BDNF plays a central role in the regulation of neuronal survival and differentiation in the human brain.

The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations

The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations

The neural correlates of subjective pleasantness

Processing of subjective pleasantness is essential in daily life decision making, particularly in the context of cognitive and environmental factors. Pleasure is mediated by a neural network and this network has been suggested to be the biological basis of pleasure including a whole range of different modalities and domains of pleasantness. This quantitative meta-analysis of brain imaging data focuses on studies 1) based on correlations between self-reported judgements of pleasantness and brain regions and investigates whether 2) immediate (during scanning) versus subsequent judgements (after scanning) differ in brain activity. We investigated concurrence across 40 studies reporting brain regions correlated with self-reported judgements of subjective pleasantness (attractiveness, liking or beauty) by means of activation likelihood estimation (ALE). Positive correlates of subjective pleasantness were found in mOFC, ventromedial prefrontal cortex, left ventral striatum, pregenual cortex, right cerebellum, left thalamus and the mid cingulate cortex. Negative correlates were found in left precentral gyrus, right cerebellum and right inferior frontal gyrus. A comparison of studies with subjective pleasantness judgement during or after scanning revealed no significant differences in brain activation. We conclude that subjective pleasantness judgements are directly related to brain regions that have been described as part of the reward circuitry (mOFC, ventral striatum). The results suggest that the evaluation of likability or pleasure is an automatic process and that it is neither elicited nor enhanced by instructions to report the outcome of these judgements.

Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait

The gene encoding cathechol-O-methyltransferase (COMT) contains a common functional missense polymorphism (Val158Met) that regulates dopamine in an allele-dependent manner. A pivotal role of dopamine neurotransmission in the prefrontal cortex has been implicated in drug-seeking behavior and related personality traits, such as sensation seeking, with some evidence for a gender-specific association. Here, we tested the hypothesis that the COMT Val158Met polymorphism modulates the personality dimension, sensation seeking, in a gender-dependent manner. Study sample included 214 male (age 38.1±12.6 years) and 218 female (age 36.1±13.6 years) healthy volunteers, who were assessed with Zuckermans sensation-seeking scale and genotyped for the Val158Met polymorphism (dbSNP:rs4680). Univariate analysis of variance showed that the sensation seeking score was significantly affected by a COMT genotype × gender interaction (F=5.330, df=2, p=0.005). The Val158Met polymorphism was associated with the sensation seeking personality trait in women only. The highest scores in the sensation-seeking scale and in three of the four subscales were observed in female subjects with the Val/Val genotype relative to women carrying the Met allele. Our results suggest that high COMT enzyme activity associated with the Val allele predisposes to high sensation seeking scores in female subjects and add to increasing evidence for a gender specific role of COMT in normal and dysfunctional behavior.

The Brain's Response to Reward Anticipation and Depression in Adolescence: Dimensionality, Specificity, and Longitudinal Predictions in a Community-Based Sample.

OBJECTIVE The authors examined whether alterations in the brains reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes. METHOD Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally. RESULTS Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses. CONCLUSIONS The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria.

Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation.

BackgroundVagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques used as therapeutic interventions in major depression.MethodsIn this study, we report the impact of these stimulation techniques on serum concentrations of brain-derived neurotrophic factor (BDNF) in treatment-resistant patients with a diagnosis of major depression.ResultsWe found no changes of BDNF serum concentrations and no association of neurotrophin concentrations in serum with clinical parameters in our sample.ConclusionOur preliminary results suggest that brain stimulation techniques—in contrast to several antidepressant medications—do not change BDNF serum concentrations.

Association of nicotinic acetylcholine receptor subunit α4 polymorphisms with nicotine dependence in 5500 Germans

Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit α4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N1=1412; N2=1855; N3=2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (⩽100 cigarettes over lifetime). We examined associations of the polymorphisms with smoking case–control status and with the extent of nicotine dependence as measured by the Fagerstrom test of nicotine dependence (FTND) score (N=1030). The most significant association was observed between rs2236196 and FTND (P=0.0023), whereas the closely linked rs1044396 had most statistical support in the case–control models (P=0.0080). The consistent effect estimates across three independent cohorts elaborate on recently published functional studies of rs2236196 from the CHRNA4 3′-untranslated region and seem to converge with accumulating evidence to firmly implicate the variant G allele of this polymorphism in the intensification of nicotine dependence.