Christoph von der Goltz

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.

Avoidance of Alcohol-Related Stimuli Increases During the Early Stage of Abstinence in Alcohol-Dependent Patients

AIMS The aim of this study was to analyse initial orienting processes as well as maintenance of attention towards alcohol cues in recently detoxified alcoholics and light social drinkers. Furthermore, we investigated the influence of pre-treatment alcohol consumption and abstinence duration onto alcohol-related attentional bias. METHODS We used an alcohol-visual-dot-probe-task with two different stimulus onset asynchronies (SOA) to examine processes of initial orienting and maintenance of attention separately (50 and 500 ms SOA). RESULTS With short SOA, we found a positive attentional bias towards alcohol cues in alcohol-dependent patients and light social drinkers that was positively associated with pre-treatment alcohol consumption in alcoholics. Using a longer SOA, a negative attentional bias was found in light social drinkers and in patients abstinent for more than 2 weeks indicating alcohol stimuli avoidance. In patients, we found a negative correlation between attentional bias and duration of abstinence. CONCLUSIONS After initial visual orienting towards alcohol-related stimuli, light social drinkers as well as longer abstinent alcohol-dependent patients disengage their attention. In patients, this disengagement increased during the first 3 weeks after detoxification indicating assimilation to the attentional bias pattern of light social drinkers.

Association of Leptin With Food Cue–Induced Activation in Human Reward Pathways

CONTEXT Overlapping neurobiological pathways between obesity and addiction disorders are currently in discussion. Whereas the hypothalamic regulation of energy homeostasis by endocrine feedback signals has been widely investigated, its interplay with mesolimbic reward-associated pathways represents a rich field of future research. OBJECTIVE To assess changes in regional brain activation in response to food-related cues in association with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and the plasma concentration of the appetite-regulating peptide leptin. DESIGN Case-control study. SETTING Academic addiction and brain imaging center, Central Institute of Mental Health, Mannheim, Germany. PARTICIPANTS Twenty-one obese subjects (BMI >30) and 23 age- and sex-matched nonobese control subjects (BMI 18.5-24.0) recruited by advertisements. MAIN OUTCOME MEASURES Regional brain activation (blood oxygen level-dependent response) in response to visual cue presentation and association of the brain activation with BMI and plasma leptin concentration. RESULTS Significant positive relationships were observed for food cue-induced brain activations in the ventral striatum in association with the plasma concentration of leptin (r = 0.27; P = .04) and with BMI (r = 0.47; P = .001). CONCLUSIONS Data suggest a physiological role of satiety factors in modulating the responsivity of mesolimbic circuits to food cues. Moreover, an altered homeostatic feedback regulation of reward pathways might explain addictionlike behavior and the inability of obese patients to adapt food intake to physiological needs.

Orexin and leptin are associated with nicotine craving: A link between smoking, appetite and reward

OBJECTIVE Preclinical data suggest modulating effects of both orexin/hypocretin and leptin on dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role of both peptides in reward function and motivation, and thus in addictive diseases. The aim of this study was to examine the possible association between orexin and leptin, and nicotine craving in smokers in a clinical case-control study under standardized conditions. METHODS We compared orexin and leptin, ACTH and cortisol plasma concentrations (RIA) between tobacco smokers (n=60) during early nicotine withdrawal and healthy controls (n=64). Motivational aspects of nicotine craving were additionally assessed in the smoking participants using the Questionnaire of Smoking Urges (QSU). RESULTS As main results we detected a significant negative correlation between orexin plasma concentration and nicotine craving (r=-0.28; p<.05), and a positive association between craving and leptin plasma concentration (r=0.29; p<.05). CONCLUSIONS Our results show an association between craving for nicotine and plasma concentrations of orexin and leptin suggesting that both peptides interfere with the dopaminergic transmission during nicotine withdrawal in a bidirectional manner and, thus, modulate craving for nicotine.

Attentional bias in alcohol-dependent patients: the role of chronicity and executive functioning.

It has been suggested that the attention towards alcohol‐related stimuli increases with the duration of drinking and alcohol dependence. The present study aimed to assess whether an attentional bias was present in detoxified alcohol‐dependent patients, and if the magnitude of the attentional bias depended on the subjects drinking history and variables of executive functioning. Attentional bias was assessed in 30 alcohol‐dependent patients using a visual dot‐probe task with a picture presentation time of 50 ms. In addition, patients completed a variety of different cognitive tasks such as attention, continuous performance, working memory, set shifting and inhibitory control tests. Based on correlation analysis we split the patient sample on the median with regard to the duration of alcohol dependence and our results indicated a significant attentional bias towards alcohol‐associated pictures in patients dependent for less than 9 years, but not in patients with a longer duration of dependence. The two patient samples differed significantly with regard to attention and working memory functioning with patients who were dependent for more than 9 years showing a greater impairment. When impairment of attention and working memory were controlled for, the group differences in attentional bias were no longer significant. Our results indicate that differences with regard to drinking‐related variables as well as cognitive functioning seem to modulate attentional bias and need to be taken into account in models of drinking maintenance.

Epigenetic alteration of the dopamine transporter gene in alcohol-dependent patients is associated with age

Chronic alcohol abuse and dependence are associated with dysfunctional dopaminergic neurotransmission in mesocorticolimbic circuits. Genetic and environmental factors have been shown to modulate susceptibility to alcohol dependence, and both may act through epigenetic mechanisms that can modulate gene expression, e.g. DNA methylation at CpG sites. Recent studies have suggested that DNA methylation patterns may change over time. However, few data are available concerning the rate of these changes in specific genes. A recent study found that hypermethylation of the promoter of the dopamine transporter (DAT) gene was positively correlated with alcohol dependence and negatively correlated with alcohol craving. The aim of the present study was to replicate these findings in a larger sample of alcohol‐dependent patients and population‐based controls matched for age and sex. No difference in methylation level was observed between patients and controls, and no difference in methylation level was observed before and after alcohol withdrawal in patients. However, patients with more severe craving showed a trend towards lower DAT methylation levels (P = 0.07), which is consistent with previous findings. Furthermore, in our overall sample, DAT methylation levels increased with age. Interestingly, a separate analysis of patients suggested that this finding was mainly driven by the patient group. Although the present data do not clarify whether chronic alcohol abuse is responsible for this phenomenon or merely enhances an ageing‐specific process, our findings suggest that hypermethylation in alcohol‐dependent patients is a consequence, rather than a cause, of the disorder.

Neurocognitive impairments in non‐deprived smokers—results from a population‐based multi‐center study on smoking‐related behavior

The aim of the present study was to examine neurocognitive function associated with chronic nicotine use. A total of 2163 healthy participants (1002 smokers, 1161 never‐smoking controls) participated in a population‐based case‐control design. The main outcome measures were six cognitive domain factors derived from a neuropsychological test battery. In smokers, the battery was administered after controlled smoking of one cigarette. Analyses included age, sex and education as covariates. Results demonstrated small, but significant deficits in smokers for visual attention (P < 0.001) and cognitive impulsivity (P < 0.006), while verbal episodic memory, verbal fluency, verbal working memory, and Stroop‐interference did not differ between groups. These attention/impulsivity deficits were also present in smokers with only a low amount of cigarette consumption. Lifetime nicotine use (pack‐years) was not correlated with cognition in smokers. In conclusion, this study confirmed subtle and specific cognitive deficits in non‐deprived smokers. The independence of these deficits from consumption intensity may argue for an a priori deficit of some cognitive abilities in smokers. These specific deficits may constitute intermediate phenotypes for genetic research on nicotine use.

Involvement of orexin in the regulation of stress, depression and reward in alcohol dependence

There is growing evidence from preclinical studies for an involvement of orexins (ORX) in the regulation of stress, affectivity and addictive behavior. The aim of our study was to gather corresponding clinical data and to elucidate the relationships between alcohol withdrawal stress, ORX plasma concentration and psychopathology. A consecutive sample of thirty-four alcohol-dependent inpatients was included in the study. Blood was drawn at onset of withdrawal and following 2 weeks of controlled abstinence in order to assess ORX, ACTH and cortisol plasma concentrations. In parallel, we assessed clinically relevant psychological distress symptoms applying the Brief Symptom Inventory (BSI). We found a significant positive correlation between ORX and global distress indices of the BSI (p ≤ 0.05). In a regression model, ORX concentration during acute withdrawal explained 24% of the variance of symptom severity (p<0.01). No association with craving, ACTH or cortisol plasma concentration was detected. Our results suggest an involvement of ORX in the affective dysregulation seen commonly in alcohol dependent patients during alcohol withdrawal. Moreover, the effects on global distress indices as well as the earlier studied effects on reinstatement of drug seeking behaviors may point on an involvement of ORX in impaired brain stress systems.

Learning and memory in the aetiopathogenesis of addiction: future implications for therapy?

Addiction is a chronic relapsing disorder. Even after long periods of abstinence from drugs, the risk of relapse, often precipitated by drug-associated cues, remains high. Especially learning processes have been shown to play a major role in the maintenance of addictive behaviour. Humans and animals rapidly learn cues and contexts that predict the availability of addictive drugs. Once learned, these cues and contexts initiate drug seeking, craving and relapse in both animal models and clinical studies. These observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. In this context, a substantial body of evidence suggests that several types of neuroadaptation occur, including synapse-specific adaptations of the type thought to underlie specific long-term associative memory. Consequently, understanding learning and memory processes in the brain in addiction is an important key for understanding the persistence of addiction, and it is reasonable to hypothesize that the disruption of drug-related memories may help to prevent relapses.