Variables involved in the cue modulation of the startle reflex in alcohol-dependent patients.

Cue modulation of the startle reflex is a paradigm that has been used to understand the emotional mechanisms involved in alcohol dependence. Attenuation of the startle reflex has been demonstrated when alcohol-dependent subjects are exposed to alcohol-related stimuli. However, the role of clinical variables on the magnitude of this response is unknown. The objective of this study was to determine the relationship between a number of clinical variables-severity of alcoholism, family history of alcoholism (FHA+), personality traits related to the sensitivity to reward-and the startle reflex response when subjects with alcohol dependence were viewing alcohol-related cues. After detoxification, 98 participants completed self-report instruments and had eye blink electromyograms measured to acoustic startle probes [100-millisecond burst of white noise at 95 dB(A)] while viewing alcohol-related pictures, and standardised appetitive, aversive and neutral control scenes. Ninety-eight healthy controls were also assessed with the same instruments. There were significant differences on alcohol-startle magnitude between patients and controls. Comparisons by gender showed that women perceived alcohol cues and appetitive cues more appetitive than men. Male and female patients showed more appetitive responses to alcohol cues when compared with their respective controls. Our patients showed an appetitive effect of alcohol cues that was positively related to severity of alcohol dependence, sensitivity to reward and a FHA+. The data confirmed that the pattern of the modulation of the acoustic startle reflex reveals appetitive effects of the alcohol cues and extended it to a variety of clinical variables.

To gamble or not to gamble: at risk for craving and relapse--learned motivated attention in pathological gambling.

In recent research similarities between pathological gambling and drug addiction have been identified, suggesting excessive gambling to constitute an addiction. So far, we have insufficient knowledge concerning the psychophysiological mechanisms underlying this kind of non-substance-related addiction. The objective of the study was to investigate emotional processing of gambling-relevant and -irrelevant stimuli in pathological gamblers and non-gambling controls using an EEG cue-reactivity paradigm. Whereas gambling-irrelevant stimuli were processed similarly in non-gambling controls (HC) and pathological gamblers (PG), PG showed significantly stronger gambling-relevant stimulus-induced psychophysiological cue-reactivity (larger gambling stimulus-induced late positive potential, LPP, higher arousal and more positively toned valence ratings as well as higher stimulus-induced craving for gambling cues compared to HC--but not the expectable increase of general craving over time and after stimulus presentation). Our findings suggest enhanced cue-reactivity in pathological gamblers indicative of learned motivated attention that may induce subjective craving and relapse.

Identifying the neural circuitry of alcohol craving and relapse vulnerability.

With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 80% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification. This article focuses on neuronal correlates of cue responses in detoxified alcoholics. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) can be associated with alcohol craving and functional brain activation in neuronal systems that process attentional relevant stimuli, reward expectancy and experience. Increased functional brain activation elicited by such alcohol-associated cues predicted an increased relapse risk, whereas high brain activity elicited by affectively positive stimuli may represent a protective factor and was correlated with a decreased prospective relapse risk. These findings are discussed with respect to psychotherapeutic and pharmacological treatment options.

Psychophysiological responses to drug-associated stimuli in chronic heavy cannabis use.

Due to learning processes originally neutral stimuli become drug-associated and can activate an implicit drug memory, which leads to a conditioned arousing 'drug-seeking' state. This condition is accompanied by specific psychophysiological responses. The goal of the present study was the analysis of changes in cortical and peripheral reactivity to cannabis as well as alcohol-associated pictures compared with emotionally significant drug-unrelated and neutral pictures in long-term heavy cannabis users. Participants were 15 chronic heavy cannabis users and 15 healthy controls. Verbal reports as well as event-related potentials of the electroencephalogram and skin conductance responses were assessed in a cue-reactivity paradigm to determine the psychophysiological effects caused by drug-related visual stimulus material. The evaluation of self-reported craving and emotional processing showed that cannabis stimuli were perceived as more arousing and pleasant and elicited significantly more cannabis craving in cannabis users than in healthy controls. Cannabis users also demonstrated higher cannabis stimulus-induced arousal, as indicated by significantly increased skin conductance and a larger late positivity of the visual event-related brain potential. These findings support the assumption that drug-associated stimuli acquire increased incentive salience in addiction history and induce conditioned physiological patterns, which lead to craving and potentially to drug intake. The potency of visual drug-associated cues to capture attention and to activate drug-specific memory traces and accompanying physiological symptoms embedded in a cycle of abstinence and relapse--even in a 'so-called' soft drug--was assessed for the first time.

Brain activation elicited by affectively positive stimuli is associated with a lower risk of relapse in detoxified alcoholic subjects.

BACKGROUND: Stimuli that are regularly associated with alcohol intake (AI) may acquire incentive salience, while other reinforcers can be devalued. We assessed whether brain activation elicited by (1) alcohol associated, (2) affectively positive, and (3) negative versus neutral stimuli is associated with the subsequent risk of relapse. METHODS: Twelve detoxified alcoholic subjects (6 women and 6 men) and 12 age-matched and gender-matched healthy control subjects were assessed with functional magnetic resonance imaging (fMRI) and a fast single-event paradigm using standardized affective and alcohol-associated pictures. Patients were followed for 6 months and AI was recorded. RESULTS: In alcoholic subjects, compared with healthy control subjects, (1) alcohol-related versus neutral visual stimuli elicited increased activation in the prefrontal (PFC; BA 6 and 10) and cingulate cortex (BA 23 and 24), precuneus and adjacent parietal cortex; (2) positive versus neutral stimuli elicited increased activation in the anterior cingulate cortex (ACC; BA 24), PFC (BA 10), ventral striatum and thalamus; and (3) negative versus neutral stimuli elicited increased activation in the PFC (BA 10). Seven alcoholic subjects relapsed. Within the follow-up period of 6 months, the number of subsequent drinking days (DD) and the amount of AI were inversely correlated with brain activation elicited by positive versus neutral stimuli in the thalamus (DD: r=-0.63, p=0.03; AI: r=-0.63, p=0.03) and in the ventral striatum (DD: r=-0.60, p=0.04; AI: r=-0.48, p=0.11). CONCLUSIONS: In this study, brain activation elicited by briefly presented alcohol-associated stimuli was not associated with the prospective risk of relapse. Unexpectedly, alcoholic subjects displayed increased limbic brain activation during the presentation of affectively positive but not negative stimuli, which may reflect a protective factor in detoxified alcoholic subjects.

Cue-induced auditory evoked potentials in alcoholism.

OBJECTIVE: Conditioning processes may convert neutral stimuli to drug-associated stimuli and create an implicit drug memory. Previous studies showed specific psychophysiological reactions to alcohol-associated stimuli differentiating alcohol-dependent subjects from healthy controls. This was shown in evoked potentials using visual and olfactory alcohol-related stimuli. METHODS: Our study examined the effects of complex alcohol-associated sounds in comparison to complex neutral sounds on electrophysiological event-related potentials and the self-report of craving. We assessed 10 detoxified alcoholics and 10 healthy controls in a cue-reactivity paradigm. RESULTS: Detoxified alcoholics demonstrated significantly higher alcohol stimulus-induced late P300 and late positive complexes. Subjective baseline craving and stimulus-induced craving only differed significantly between groups in terms of the craving dimension "relief of withdrawal symptoms". CONCLUSIONS: The results show that auditory stimuli attach importance to stimulus-induced craving in alcoholics. Therapeutic consequences will be discussed. SIGNIFICANCE: The study examined for the first time the effects of alcohol-associated auditory stimuli on alcohol craving and identifies learning processes as underlying neural mechanisms which support the assumption of an implicit addiction memory in alcoholics.

The influence of current mood on affective startle modulation.

The affect-modulated startle response is a reliable indicator of the affective processing of stimuli. It may be influenced by trait and state affective variables as well as psychopathological status. The aim of the present study was to determine the influence of the current mood state on startle modulation. Forty-five healthy volunteers viewed affective stimuli while eye blink responses and subjective emotional ratings were assessed. In addition, the current state of mood was assessed, pre and post the experimental procedure. Subjects were divided into those that were in a more positive and those that were in a more negative mood based on a median split. Compared to subjects in a positive mood those in a more negative mood showed significantly reduced startle amplitudes after viewing the negative and neutral stimuli. The results of the present study show that changes in startle responses are not only related to the current state of psychopathology but also to the general affective state of the participants during the assessments.

Diagnostic instruments for behavioural addiction: an overview.

In non-substance-related addiction, the so-called behavioural addiction, no external psychotropic substances are consumed. The psychotropic effect consists of the body's own biochemical processes induced only by excessive activities. Until recently, knowledge was limited with respect to clinically relevant excessive reward-seeking behaviour, such as pathological gambling, excessive shopping and working which meet diagnostic criteria of dependent behaviour. To date, there is no consistent concept for diagnosis and treatment of excessive reward-seeking behaviour, and its classification is uncertain. Therefore, a clear conceptualization of the so-called behavioural addictions is of great importance. The use of adequate diagnostic instruments is necessary for successful therapeutical implications.This article provides an overview of the current popular diagnostic instruments assessing the different forms of behavioural addiction. Especially in certain areas there are only few valid and reliable instruments available to assess excessive rewarding behaviours that fulfill the criteria of addiction.

Alcohol craving in problem and occasional alcohol drinkers.

AIMS: The impact of emotional states on alcohol craving has so far mainly been investigated in abstinent and actively consuming alcohol addicts. Alcohol craving and the variables that influence alcohol craving have not yet been examined in non-addicted, alcohol abusing drinkers and non-abusing occasional alcohol drinkers. METHODS: In this study 50 problem drinkers and 50 occasional alcohol drinkers were investigated. The impact of various craving-related variables such as stress and distress, alcohol effect expectancies, and stress coping strategies on reward and relief craving was examined and compared between the groups. RESULTS: Whereas most occasional drinkers reported little alcohol craving, problem drinkers showed a significantly higher amount of reward and relief craving accompanied by increased levels of stress-distress and a stronger tendency to use negative (inadequate) coping strategies. Stress-distress and alcohol effect expectancies were significant predictors of reward and relief craving in problem drinkers. In occasional drinkers alcohol craving was not related to any of these variables. These variables were also found to be predictive of craving in alcohol addicts. CONCLUSIONS: We hypothesized, that in non-addicted problem drinkers the expected rewarding and reinforcing alcohol effects lead to an early stage of addictive behaviour. Therefore, in this stage therapeutic interventions focussing on the awareness of the function of alcohol intake as well as alternative coping skills might be useful to prevent alcohol dependence in problem drinkers.

A new approach to preventing relapse in opiate addicts: a psychometric evaluation.

The present study investigated psychological aspects after different methods of withdrawal treatments in opiate addicts had been conducted. Two pharmacological strategies based on delivering an opioid agonist or antagonist were used for withdrawal in opiate addicts. After detoxification, the antagonist was delivered by a pellet implanted subcutaneously. Four days after the beginning of the treatment several psychological variables such as craving, anxiety, depression, and mood were assessed and compared with data from actively consuming opiate addicts and healthy controls. In addition, 6 and 12 weeks later the relapse rates were assessed. Compared with addicts detoxified and treated with Levomethadone as well as actively heroin consuming addicts, subjects treated with Naltrexone demonstrated significantly higher positive psychological outcome concerning all assessed variables and significantly lower relapse rates. Naltrexone implants prove prevention of relapse during the most vulnerable period after detoxification. Compared with Levomethadone withdrawal, they lead to a significantly better psychological condition in patients.

[Excessive computer usage in adolescents--results of a psychometric evaluation]. / Exzessive Computernutzung im Kindesalter--Ergebnisse einer psychometrischen Erhebung.

Excessive computer and video game playing among children is being critically discussed from a pedagogic and public health point of view. To date, no reliable data for this phenomenon in Germany exists. In the present study, the excessive usage of computer and video games is seen as a rewarding behavior which can, due to learning mechanisms, become a prominent and inadequate strategy for children to cope with negative emotions like frustration, uneasiness and fears. In the survey, 323 children ranging in age from 11 to 14 years were asked about their video game playing behavior. Criteria for excessive computer and video game playing were developed in accordance with the criteria for dependency and pathological gambling (DSM-IV, ICD-10). Data show that 9.3% (N = 30) of the children fulfill all criteria for excessive computer and video game playing. Furthermore, these children differ from their class mates with respect to watching television, communication patterns, the ability to concentrate in school lectures and the preferred strategies coping with negative emotions. In accordance with findings in studies about substance-related addiction, data suggest that excessive computer and video game players use their excessive rewarding behavior specifically as an inadequate stress coping strategy.

Immigration-associated variables and substance dependence.

OBJECTIVE: Drug-dependent patients show increased negative mood states such as anxiety and depression that interact with drug craving and quality of life. In this study, we compared immigrants with and without drug dependence and assessed whether drug dependence and social status after immigration contributed independently to negative mood states, stress-coping strategies and satisfaction with life in Germany. METHOD: Immigrants (N = 80) who had emigrated from the former Soviet Union to Germany were participants in the study. Drug-dependent immigrants (24 men, 16 women, mean [SD] age 33 [9] years) were compared with healthy immigrants (26 men, 14 women, mean age 35 [12] years) on current emotional status, trait-anxiety, depression, stress-coping strategies, drug craving and immigration-associated data. RESULTS: Compared with healthy immigrants, drug-dependent immigrants showed significantly higher levels of anxiety, depression and negative stress-coping strategies, independent of differences in education or employment status. Satisfaction with being in Germany was associated with both drug dependence and employment status. The severity of drug craving was significantly associated with negative mood states but not with any other measured sociodemographic variable. CONCLUSIONS: This study shows that drug dependence is associated with increased negative mood states and poor stress-coping strategies, independent of the assessed sociodemographic variables. Drug dependence may thus severely interfere with acculturation in the host country. Because immigrants often face reduced treatment options as a result of cultural and language barriers, our findings underline the importance of adequate drug treatment facilities for dependent immigrants.

Localization of the human female breast in primary somatosensory cortex.

RATIONALE: Despite an extensive body of research on the topography of the primary somatosensory cortex (S1) little is known about the representation of the trunk. AIM: The aim of this study was to determine the representation of the breast in S1 in human females. RESULTS: The representation of the human breast in primary somatosensory cortex was determined in ten healthy female subjects. Non-painful electrical stimulation of the mammilla (Th4 dermatome), groin (L1 dermatome) and the first digit of both sides of the body activated cutaneous receptors and thus elicited somatosensory evoked potentials. The representation of these body parts in primary somatosensory cortex (S1) was determined using neuroelectric source imaging. Equivalent current dipole localizations were overlaid with individual structural magnetic resonance images to account for individual cortical differences. The breast representation was localized between the representation of the groin and the first digit. In the medial-lateral direction the representation of the breast was approximately 15 mm lateral of the longitudinal fissure in the contralateral hemisphere. Source localizations were stable across subjects. However, one subject showed ipsilateral representation of the breast, which might be related to bilateral receptive fields of the ventral body midline representation. This study confirms the Penfield and Rasmussen (1950) invasive data by use of noninvasive source imaging.

The assessment of craving: psychometric properties, factor structure and a revised version of the Alcohol Craving Questionnaire (ACQ).

AIMS: The goal of the present study was to examine the psychometric properties and factor structure of the Alcohol Craving Questionnaire (ACQ). DESIGN AND PARTICIPANTS: The German version of the ACQ was administered to a sample of 243 alcohol-dependent or alcohol-abusing subjects. A subgroup of the sample (n = 46) completed the German translation of the Obsessive Compulsive Drinking Scale (OCDS) and the ACQ a second time. MEASUREMENTS: To validate the factor models, confirmatory factor analyses (CFA) were carried out. Examination of the psychometric properties of the ACQ included the analysis of the item characteristics to exclude non-sensitive items, an exploratory factor analysis of the remaining items and calculation of internal consistency, test-retest reliability and convergent validity. FINDINGS: Neither of the two models showed a satisfactory correspondence. An exploratory factor analysis of a revised version of the ACQ (ACQ-R), based on the psychometric properties of the items, revealed two stable factors ('urge and intention to drink alcohol' and 'reinforcement') with high internal consistency, test-retest reliability and convergent validity. The model fit was also excellent in the CFA. CONCLUSIONS: The ACQ-R is a reliable and valid instrument to assess alcohol craving. However, the ACQ-R lacks items related to loss of control. Therefore a multi-dimensional assessment, e.g. the combination of the ACQ-R and the OCDS, is recommended.

Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex.

Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A functional polymorphism in the COMT gene (val158met) accounts for a fourfold variation in enzyme activity. The low-activity met158 allele has been associated with improved working memory but with higher risk for anxiety-related behaviors. Using functional magnetic resonance imaging, we assessed the effects of COMT genotype on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 35 healthy subjects. The analysis of genotype effects was restricted to brain areas with robust activation by the task. To determine genedose effects, the number of met158 alleles (0, 1, or 2) was correlated with the blood oxygen level-dependent (BOLD) response elicited by pleasant or unpleasant stimuli compared with neutral stimuli. COMT genotype had no significant impact on brain activation by pleasant stimuli but was related to the neural response to unpleasant stimuli: reactivity to unpleasant stimuli was significantly positively correlated with the number of met158 alleles in the limbic system (left hippocampus, right amygdala, right thalamus), connected prefrontal areas (bilateral ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex), and the visuospatial attention system (bilateral fusiform gyrus, left inferior parietal lobule). Genotype explained up to 38% of interindividual variance in BOLD response elicited by unpleasant stimuli. We conclude that (1) genetic variations can account for a substantial part of interindividual variance in task-related brain activation and that (2) increased limbic and prefrontal activation elicited by unpleasant stimuli in subjects with more met158 alleles might contribute to the observed lower emotional resilience against negative mood states.

Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter.

Major depression is conditionally linked to a polymorphism of the human serotonin transporter gene (SLC6A4). During the presentation of aversive, but not pleasant, pictures, healthy carriers of the SLC6A4 short (s) allele showed stronger activation of the amygdala on functional magnetic resonance imaging. s carriers also showed greater coupling between the amygdala and the ventromedial prefrontal cortex, which may contribute to the abnormally high activity in the amygdala and medial prefrontal cortex seen in major depression.

Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving.

OBJECTIVE: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D(2) receptors, and delayed recovery of D(2) receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged D(2) receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli. METHOD: Multimodal imaging, with the radioligand [(18)F]desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the association of D(2)-like dopamine receptors in the ventral striatum with alcohol craving and central processing of alcohol cues. RESULTS: Activation of the medial prefrontal cortex and striatum by alcohol-associated stimuli, relative to activation by neutral visual stimuli, was greater in the detoxified alcoholics than in the healthy men. The alcoholics displayed less availability of D(2)-like receptors in the ventral striatum, which was associated with alcohol craving severity and with greater cue-induced activation of the medial prefrontal cortex and anterior cingulate as assessed with fMRI. DISCUSSION: In alcoholics, dopaminergic dysfunction in the ventral striatum may attribute incentive salience to alcohol-associated stimuli, so that alcohol cues elicit craving and excessive activation of neural networks associated with attention and behavior control.

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics.

RATIONALE: Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior. OBJECTIVES: Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients. METHODS: We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded. RESULTS: Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning. CONCLUSIONS: This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.

[Excessive compulsive buying or "behavioral addiction"? A case study]. / Exzessives, zwanghaftes Kaufen oder "Verhaltenssucht"? Ein Fallbeispiel.

Compulsive buying is characterized by repetitive compulsive and excessive misappropriated buying. Labels for this pathological behavior vary and its classification is uncertain. To date, there is no consistent concept for diagnosis and treatment. We present the case of a 36-year old woman with a history of excessive pathological buying. According to the assumption that addiction is a learned behavior, we assume that for the patient compulsive buying as a rewarding behavior has the function of an inadequate stress coping strategy. Therefore, in this case the diagnosis "non-substance-related behavioral addiction" is appropriate. This diagnosis is important for the choice of the therapeutic intervention, which is in accordance to the current therapeutic interventions for substance-related addictions.

Determination of naltrexone and 6-beta-naltrexol in human plasma following implantation of naltrexone pellets using gas chromatography-mass spectrometry.

An alternative to detoxification by oral therapy with the narcotic antagonist naltrexone is the subcutaneous implantation of naltrexone pellets. From detoxified patients with naltrexone implants (1g) 26 blood samples were collected up to 73 days after implantation. The assay for naltrexone and 6-beta-naltrexol in plasma was developed using automated mixed-mode solid-phase extraction, catalysed trimethylsilylation and gas chromatography-mass spectrometry in single ion monitoring mode with naloxone as internal standard. The analytical method was very sensitive with limits of detection of 0.1 ng/ml and was linear up to 60 ng/ml for naltrexone and 200 ng/ml for naltrexol. Intra-day precision for naltrexone and naltrexol were 24.3 and 22.9%, respectively, at the LLOQ (accuracy 1.4 and 0.4%, respectively) and less than 10% (2.0, 6.0 and 20.0 ng/ml, n = 6 each) above. Inter-day precision was 7.9% (accuracy -0.6%) for naltrexone and 10.9% (accuracy 1.6%) for naltrexol (20 ng/ml, n = 10). Extraction recoveries were 83% for both analytes (10 ng/ml, n = 6). The concentrations of naltrexone and naltrexol in the plasma samples were in the range of 0.7-13.7 and 0.9-17.0 ng/ml, respectively. The simple analytical procedure described provided good sensitivity for the assay of naltrexone and naltrexol in plasma after naltrexone pellet implantation.