Anne Jorde

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.

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.

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.

Cortical surface-based threshold-free cluster enhancement and cortexwise mediation: Cortical Surface Statistics and Mediation

Threshold‐free cluster enhancement (TFCE) is a sensitive means to incorporate spatial neighborhood information in neuroimaging studies without using arbitrary thresholds. The majority of methods have applied TFCE to voxelwise data. The need to understand the relationship among multiple variables and imaging modalities has become critical. We propose a new method of applying TFCE to vertexwise statistical images as well as cortexwise (either voxel‐ or vertexwise) mediation analysis. Here we present TFCE_mediation, a toolbox that can be used for cortexwise multiple regression analysis with TFCE, and additionally cortexwise mediation using TFCE. The toolbox is open source and publicly available (https://github.com/trislett/TFCE_mediation). We validated TFCE_mediation in healthy controls from two independent multimodal neuroimaging samples (N = 199 and N = 183). We found a consistent structure–function relationship between surface area and the first independent component (IC1) of the N‐back task, that white matter fractional anisotropy is strongly associated with IC1 N‐back, and that our voxel‐based results are essentially identical to FSL randomise using TFCE (all PFWE<0.05). Using cortexwise mediation, we showed that the relationship between white matter FA and IC1 N‐back is mediated by surface area in the right superior frontal cortex (PFWE < 0.05). We also demonstrated that the same mediation model is present using vertexwise mediation (PFWE < 0.05). In conclusion, cortexwise analysis with TFCE provides an effective analysis of multimodal neuroimaging data. Furthermore, cortexwise mediation analysis may identify or explain a mechanism that underlies an observed relationship among a predictor, intermediary, and dependent variables in which one of these variables is assessed at a whole‐brain scale. Hum Brain Mapp 38:2795–2807, 2017.

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.