Martina Kirsch

Effects of Cue-Exposure Treatment on Neural Cue Reactivity in Alcohol Dependence: A Randomized Trial

BACKGROUND In alcohol-dependent patients, alcohol-associated cues elicit brain activation in mesocorticolimbic networks involved in relapse mechanisms. Cue-exposure based extinction training (CET) has been shown to be efficacious in the treatment of alcoholism; however, it has remained unexplored whether CET mediates its therapeutic effects via changes of activity in mesolimbic networks in response to alcohol cues. In this study, we assessed CET treatment effects on cue-induced responses using functional magnetic resonance imaging (fMRI). METHODS In a randomized controlled trial, abstinent alcohol-dependent patients were randomly assigned to a CET group (n = 15) or a control group (n = 15). All patients underwent an extended detoxification treatment comprising medically supervised detoxification, health education, and supportive therapy. The CET patients additionally received nine CET sessions over 3 weeks, exposing the patient to his/her preferred alcoholic beverage. Cue-induced fMRI activation to alcohol cues was measured at pretreatment and posttreatment. RESULTS Compared with pretreatment, fMRI cue-reactivity reduction was greater in the CET relative to the control group, especially in the anterior cingulate gyrus and the insula, as well as limbic and frontal regions. Before treatment, increased cue-induced fMRI activation was found in limbic and reward-related brain regions and in visual areas. After treatment, the CET group showed less activation than the control group in the left ventral striatum. CONCLUSIONS The study provides first evidence that an exposure-based psychotherapeutic intervention in the treatment of alcoholism impacts on brain areas relevant for addiction memory and attentional focus to alcohol-associated cues and affects mesocorticolimbic reward pathways suggested to be pathophysiologically involved in addiction.

Validating incentive salience with functional magnetic resonance imaging: association between mesolimbic cue reactivity and attentional bias in alcohol‐dependent patients

Alcohol‐associated cues are able to elicit brain activations in mesocorticolimbic networks that are related to the rewarding properties of the drug. Some authors hypothesize that the activation of the mesocorticolimbic reward system triggers an attention allocation to alcohol‐associated cues. Yet, no functional magnetic resonance imaging (fMRI) studies examining this proposition are available. In this fMRI study we investigate the association between attentional bias and neural cue reactivity. Thirty‐eight recently abstinent alcohol‐dependent patients were examined. fMRI was used to study cue reactivity during the presentation of alcohol‐related pictures. A modified visual dot‐probe task was used to assess attentional bias. Alcohol‐dependent patients showed an attentional bias to alcohol‐associated cues as well as cue‐induced fMRI activation in response to alcohol‐related stimuli in limbic and reward‐related brain regions and visual areas. We found a positive correlation between cue‐induced brain activation and attentional bias score in a network including frontal, temporal and subcortical regions. This study is the first demonstrating that, in line with previous suggestions, cue induced activation of the mesocorticolimbic reward system triggers focusing attention to substance‐associated cues. However, this association could also be bidirectional with the attentional bias enhancing cue‐induced neural activity.

Cerebellar and Hippocampal Activation During Eyeblink Conditioning Depends on the Experimental Paradigm: A MEG Study

The cerebellum and the hippocampus are key structures for the acquisition of conditioned eyeblink responses. Whereas the cerebellum seems to be crucial for all types of eyeblink conditioning, the hippocampus appears to be involved only in complex types of learning. We conducted a differential conditioning study to explore the suitability of the design for magnetencephalography (MEG). In addition, we compared cerebellar and hippocampal activation during differential delay and trace conditioning. Comparable conditioning effects were seen in both conditions, but a greater resistance to extinction for trace conditioning. Brain activation differed between paradigms: delay conditioning provoked activation only in the cerebellum and trace conditioning only in the hippocampus. The results reflect differential brain activation patterns during the two types of eyeblink conditioning.

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.

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.

Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence

According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol‐associated cues, diminished motivation to pursue non‐drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non‐drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol‐dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task‐related brain activation and connectivity. Alcohol‐dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit.

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.

Association of the alcohol dehydrogenase gene polymorphism rs1789891 with gray matter brain volume, alcohol consumption, alcohol craving and relapse risk: ADH gene effects in alcoholism

Alcohol metabolizing enzymes, such as the alcohol dehydrogenases and the aldehyde dehydrogenases, regulate the levels of acetaldehyde in the blood and play an important role in the development and maintenance of alcohol addiction. Recent genome‐wide systematic searches found associations between a single nucleotide polymorphism (rs1789891, risk allele: A, protective allele: C) in the alcohol dehydrogenase gene cluster and the risk of alcohol dependence. The current study investigated the effect of this single nucleotide polymorphism on alcohol consumption, craving for alcohol, relapse risk and brain gray matter volume. Alcohol‐dependent patients (n = 74) and controls (n = 43) were screened, genotyped and underwent magnetic resonance imaging scanning, and relapse data were collected during 3 months following the experiment. Alcohol‐dependent A allele carriers reported increased alcohol craving and higher alcohol consumption compared with the group of alcohol‐dependent individuals homozygous for the C allele, which displayed craving values similar to the control group. Further, follow‐up data indicated that A allele carriers relapsed earlier to heavy drinking compared with individuals with two C alleles. Analyses of gray matter volume indicated a significant genotype difference in the patient group: individuals with two C alleles had reduced gray matter volume in the left and right superior, middle and inferior temporal gyri.

Frontostriatal Connectivity During Reward Anticipation

Neurobiological research indicates that altered reward processing is among the most promising risk mechanisms in alcohol use disorder and depression. To elucidate differences and similarities between both disorders, we investigated clinical patients and at-risk individuals in two studies using a functional magnetic resonance imaging (fMRI) monetary reward paradigm. In the first study, alcohol use disorder patients compared to depressed and healthy individuals showed increased activation of the ventral striatum during reward anticipation. In contrast, both patient groups showed reduced frontostriatal connectivity compared to controls. In the second study, at-risk comorbid individuals showed decreased activation in the dorsal striatum along with decreased frontostriatal connectivity. While the connectivity results replicate the common pattern found for the patient groups, the activation results indicate a more depression-related pattern in individuals prone to developing both disorders. In conclusion, frontostriatal connectivity might be a promising transdiagnostic marker for depression, alcohol use disorder, and their comorbidity.