Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues

BACKGROUND: Functional imaging studies have recently demonstrated that specific brain regions become active in cocaine addicts when they are exposed to cocaine stimuli. To test whether there are regional brain activity differences during alcohol cue exposure between alcoholic subjects and social drinkers, we designed a functional magnetic resonance imaging (fMRI) protocol involving alcohol-specific cues. METHODS: Ten non-treatment-seeking adult alcoholic subjects (2 women) (mean [SD] age, 29.9 [9.9] years) as well as 10 healthy social drinking controls of similar age (2 women) (mean [SD] age, 29.4 [8.9] years) were recruited, screened, and scanned. In the 1.5-T magnetic resonance imaging scanner, subjects were serially rated for alcohol craving before and after a sip of alcohol, and after a 9-minute randomized presentation of pictures of alcoholic beverages, control nonalcoholic beverages, and 2 different visual control tasks. During picture presentation, changes in regional brain activity were measured with the blood oxygen level-dependent technique. RESULTS: Alcoholic subjects, compared with the social drinking subjects, reported higher overall craving ratings for alcohol. After a sip of alcohol, while viewing alcohol cues compared with viewing other beverage cues, only the alcoholic subjects had increased activity in the left dorsolateral prefrontal cortex and the anterior thalamus. The social drinkers exhibited specific activation only while viewing the control beverage pictures. CONCLUSIONS: When exposed to alcohol cues, alcoholic subjects have increased brain activity in the prefrontal cortex and anterior thalamus-brain regions associated with emotion regulation, attention, and appetitive behavior.     

Physiological and subjective responding to alcohol cue exposure in alcoholics and control subjects: evidence for appetitive responding

Summary. 36 alcoholic patients, recruited from a treatment program, and 20 non-alcohol abusing control subjects were tested for their reactions to alcohol and non-alcohol cues. The cue exposure paradigm included audio-visual (video), tactile, olfactory, and guided imagery cue components related to alcohol and non-alcohol beverages. Response measures were analyzed for significant difference based on alcohol and non-alcohol cue and patient type. Among the subjective ratings, alcohol cue specific increases in alcohol craving, desire to drink, alcohol-like high, positive drinking expectancies and alcohol-like withdrawal were seen in alcoholic subjects. Among the physiological measures, alcohol cue specific increases in salivation were seen in alcoholic subjects. Changes in heart rate, skin conductance and temperature were not specific to alcohol cues, or to alcoholic patients. The smelling of alcohol had the greatest impact on alcohol craving and skin conductance in alcoholic subjects. These findings demonstrate robust subjective effects, and weak physiological effects, in response to a multidimensional alcohol cue exposure paradigm. The response profile indicates cue reactivity in alcoholics as an appetitive based form of alcohol craving.     

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.     

The influence of gender and emotional valence of visual cues on FMRI activation in humans

Emotional neuroscience maps neurocircuits associated with the processing of affective stimuli. To assess gender differences in brain activation elicited by affective stimuli, we used pictures from the International Affective Picture System in a functional magnetic resonance imaging (fMRI) study. Ten male and ten female age-matched healthy volunteers were included and viewed affectively negative versus positive pictures, which were presented in an event related design. There was a significant interaction between valence of emotional stimuli and gender in the sublenticular extended amygdala (SLEA) and the rostral anterior cingulate. fMRI activation in these regions was stronger for negative compared to positive cues in women. In men fMRI activation was independent of stimulus valence. These results suggest to take gender differences into account when emotional paradigms are tested in functional brain imaging.     

Development of stimulus material for research in alcohol use disorders

The availability of appropriate stimulus material is a key concern for an experimental approach to research on alcohol use disorders (AUDs). A large number of such stimuli are necessary to evoke relevant alcohol‐related associations. We report the development of a large stimulus database consisting of 457 pictures of alcoholic beverages and 398 pictures of neutral objects. These stimuli were rated by 18 inpatients hospitalized due to severe AUD and 18 healthy controls along four dimensions: arousal, valence, alcohol‐relatedness, and craving. Physical parameters of the pictures were assessed. After outlier removal, 831 stimuli that were characterized as either alcohol‐related or neutral were retained in the final stimulus pool. Alcohol‐related pictures (versus neutral pictures) evoked higher arousal, more craving and were judged to have higher alcohol‐relatedness and a more negative valence. Group comparisons indicated that in patients, neutral pictures evoked more craving and had higher alcohol‐relatedness than they did in controls. Physical parameters such as visual complexity, luminance, and color were extracted from these pictures, and extreme values were normalized to minimize mean differences between alcoholic and neutral stimuli. The pictures met the qualitative requirements for (neurophysiological) research. A data file containing rating values and physical parameters will be provided upon request.     

Cue-induced alcohol craving. Neurobiological correlates and clinical relevance

If there is no further intervention, relapse rates in detoxified alcoholics are high, up to 85%, even after complete remission of bodily withdrawal symptoms. It has been suggested that one relevant mechanism contributing to the relapse risk is the exposure to stimuli (cues) that have regularly been associated with alcohol intake. Such stimuli can become conditioned cues that elicit alcohol craving and intake as conditioned responses. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic, and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) is associated with alcohol craving and brain activation elicited by alcohol-associated pictures. These findings point to specific indications for psychotherapeutic and additive pharmacological treatment options.     

Problematic alcohol use and mild intellectual disability: standardization of pictorial stimuli for an alcohol cue reactivity task

The present study focused on the first step in developing a cue reactivity task for studying cognitive biases in individuals with mild to borderline intellectual disability (ID) and alcohol use-related problems: the standardization of pictorial stimuli. Participants (N=40), both with and without a history of alcohol use-related problems and varying in IQ, were admitted to a forensic setting and were all abstinent. They were asked to rate familiarity, complexity, valence and attractiveness of pictures portraying both alcoholic and non-alcoholic beverages. There was a tendency to rate non-alcoholic beverages as more pleasant and attractive than alcoholic beverages. In participants with mild to borderline ID, this difference reached statistical significance, even when controlling for alcohol use-related problems in the past. The overall result of the study is a large database of 255 pictures portraying both alcoholic and non-alcoholic beverages that will be used to validate an implicit measure of cognitive biases for alcohol in individuals with mild to borderline ID.     

Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients

CONTEXT In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. OBJECTIVE To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. DESIGN A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. SETTING Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. PARTICIPANTS A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects MAIN OUTCOME MEASURES Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. RESULTS Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. CONCLUSIONS Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.     

Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study

To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs-suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.     

Stimulus-induced craving and startle potentiation in abstinent alcoholics and controls.

Abstinent alcoholics often deny craving for alcohol but still show a high level of relapse. The eyeblink response to startling noise was used as an indicator of the emotional response to alcohol-related, positive, negative and neutral visual stimuli in abstinent alcoholics, social drinkers and rarely drinking controls. The cognitive evaluation of the stimuli was assessed by ratings of subjective craving, valence and arousal. The startle response of the alcoholics to alcohol-related stimuli was significantly inhibited despite an aversive overt stimulus-evaluation. These findings indicate that alcohol-related stimuli may have appetitive incentive salience for alcoholics in spite of verbal reports of craving and valence to the opposite.     

Dissociation of emotional processes in response to visual and olfactory stimuli following frontotemporal damage

Contemporary neuropsychological studies have stressed the widely distributed and multicomponential nature of human affective processes. Here, we examined facial electromyographic (EMG) (zygomaticus and corrugator muscle activity), autonomic (skin conductance and heart rate) and subjective measures of affective valence and arousal in patient TG, a 30 year-old man with left anterior mediotemporal and left orbitofrontal lesions resulting from a traumatic brain injury. Both TG and a normal control group were exposed to hedonically valenced visual and olfactory stimuli. In contrast with control subjects, facial EMG and electrodermal activity in TG did not differentiate among pleasant, unpleasant and neutral pictures. In addition, the controls reacted spontaneously with larger corrugator EMG activity and higher skin conductance to unpleasant odors. By contrast, the subjective feeling states (pleasure and arousal ratings) remained preserved in TG. The covariation between facial and self-report measures of negative valence was also a function of the nature of the olfactory task in the patient only. Taken together, the data suggest a functional dissociation between brain substrates supporting generation of emotion and those supporting representation of emotion.     

Dissociation of emotional processes in response to visual and olfactory stimuli following frontotemporal damage

Contemporary neuropsychological studies have stressed the widely distributed and multicomponential nature of human affective processes. Here, we examined facial electromyographic (EMG) (zygomaticus and corrugator muscle activity), autonomic (skin conductance and heart rate) and subjective measures of affective valence and arousal in patient TG, a 30 year-old man with left anterior mediotemporal and left orbitofrontal lesions resulting from a traumatic brain injury. Both TG and a normal control group were exposed to hedonically valenced visual and olfactory stimuli. In contrast with control subjects, facial EMG and electrodermal activity in TG did not differentiate among pleasant, unpleasant and neutral pictures. In addition, the controls reacted spontaneously with larger corrugator EMG activity and higher skin conductance to unpleasant odors. By contrast, the subjective feeling states (pleasure and arousal ratings) remained preserved in TG. The covariation between facial and self-report measures of negative valence was also a function of the nature of the olfactory task in the patient only. Taken together, the data suggest a functional dissociation between brain substrates supporting generation of emotion and those supporting representation of emotion.     

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.     

Gender differences in the processing of disgust- and fear-inducing pictures: an fMRI study

We examined whether males and females differ in the intensity and laterality of their hemodynamic responses towards visual disgust and fear stimuli. Forty-one female, and 51 male subjects viewed disgust-inducing, fear-inducing and neutral pictures in an fMRI block design. Self-report data indicated that the target emotions had been elicited successfully with women responding stronger than men. While viewing the fear pictures, which depicted attacks by humans or animals, men exhibited greater activation in the bilateral amygdala and the left fusiform gyrus than women. This response pattern may reflect greater attention from males to cues of aggression in their environment. Further, the lateralization of brain activation was comparable in the two genders during both aversive picture conditions.     

Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders

The purpose of the present study was to establish a short paradigm for the examination of classical aversive conditioning processes for application in patients with anxiety disorders. We measured behavioral, autonomic and neural correlates of the paradigm in healthy subjects, applying functional magnetic resonance imaging (fMRI) and measurement of skin conductance. Therefore, neutral visual stimuli were paired with an unpleasant white noise as unconditioned stimulus. Twenty healthy subjects performed three experimental phases of learning: familiarization, acquisition and extinction. Subjective ratings of valence and arousal after each phase of conditioning as well as skin conductance measurement indicated successful conditioning. During acquisition, fMRI results showed increased activation for the conditioned stimulus (CS+_unpaired) when compared with the non-conditioned stimulus (CS−) in the right amygdala, the insulae, the anterior cingulate cortex and the parahippocampal gyrus, all regions known to be involved in emotional processing. In addition, a linearly decreasing activation in the right amygdala/hippocampus for the CS− across the acquisition phase was found. There were no significant differences between CS+ and CS− during extinction. In conclusion, the applicability of this paradigm for the evaluation of neural correlates in conditioning and extinction processes has been proven. Thus, we present a promising paradigm for the examination of the fear-circuit in patients with anxiety disorders and additionally effects of cognitive-behavioral interventions.     

Brain activity underlying emotional valence and arousal: a response-related fMRI study

Emotional behavior is organized along two psychophysiologic dimensions: (1) valence, varying from negative to positive, and (2) arousal, varying from low to high. Behavioral responses along these dimensions are assumed to be mediated by different brain circuits. We recorded startle reflex modulation and skin conductance responses in healthy volunteers during functional magnetic resonance imaging (fMRI) while they viewed a set of emotional pictures and took verbal ratings of the emotional valence and arousal of each picture after scanning. Response-related multiple correlation analysis revealed differential brain activity in five brain regions. Startle reflex changes, associated with the valence of a stimulus, correlated with activity in the amygdala, while verbal reports of negative emotional valence varied with insular activity. Peripheral physiologic and verbal responses along the arousal dimension varied with thalamic and frontomedial activity. Peripheral physiologic responses along both dimensions correlated with activity in somatosensory association areas in the anterior parietal cortex. In the valence dimension, activity in the left anterior parietal cortex was associated with highly correlating peripheral physiologic and verbal responses, suggesting that verbal reports of emotional valence might depend partly on brain circuits representing peripheral physiologic changes. Our data provide direct evidence for a functional segregation of brain structures underlying peripheral physiologic responses and verbal ratings along the emotional dimensions of valence and arousal.     

Symptom provocation and reduction in patients suffering from spider phobia

Neurofunctional mechanisms underlying cognitive behavior therapy (CBT) are still not clearly understood. This functional magnetic resonance imaging (fMRI) study focused on changes in brain activation as a result of one-session CBT in patients suffering from spider phobia. Twenty-six female spider phobics and 25 non-phobic subjects were presented with spider pictures, generally disgust-inducing, generally fear-inducing and affectively neutral scenes in an initial fMRI session. Afterwards, the patients were randomly assigned to either a therapy group (TG) or a waiting list group (WG). The scans were repeated one week after the treatment or after a one-week waiting period. Relative to the non-phobic participants, the patients displayed increased activation in the amygdala and the fusiform gyrus as well as decreased activation in the medial orbitofrontal cortex (OFC) during the first exposure. The therapy effect consisted of increased medial OFC activity in the TG relative to the WG. Further, therapy-related reductions in experienced somatic anxiety symptoms were positively correlated with activation decreases in the amygdala and the insula. We conclude that successful treatment of spider phobia is primarily accompanied by functional changes of the medial OFC. This brain region is crucial for the self-regulation of emotions and the relearning of stimulus-reinforcement associations.     

Brain responses to emotional salience and reward in alcohol use disorder

Heightened neural responsiveness of alcoholics to alcohol cues and social emotion may impede sobriety. To test mesocorticolimbic network responsivity, 10 (8 men) alcohol use disorder (AUD) patients sober for 3 weeks to 10 months and 11 (8 men) controls underwent fMRI whilst viewing pictures of alcohol and non-alcohol beverages and of emotional faces (happy, sad, angry). AUD and controls showed similarities in mesocorticolimbic activity: both groups activated fusiform for emotional faces and hippocampal and pallidum regions during alcohol picture processing. In AUD, less fusiform activity to emotional faces and more pallidum activity to alcohol pictures were associated with longer sobriety. Using graph theory-based network efficiency measures to specify the role of the mesocorticolimbic network nodes for emotion and reward in sober AUD revealed that the left hippocampus was less efficiently connected with the other task-activated network regions in AUD than controls when viewing emotional faces, while the pallidum was more efficiently connected when viewing alcohol beverages. Together our findings identified lower occipito-temporal sensitivity to emotional faces and enhanced striatal sensitivity to alcohol stimuli in AUD than controls. Considering the role of the striatum in encoding reward, its activation enhancement with longer sobriety may reflect adaptive neural changes in the first year of drinking cessation and mesocorticolimbic system vulnerability for encoding emotional salience and reward potentially affecting executive control ability and relapse propensity during abstinence.     

Dissociable neural effects of stimulus valence and preceding context during the inhibition of responses to emotional faces

Socially appropriate behavior requires the concurrent inhibition of actions that are inappropriate in the context. This self‐regulatory function requires an interaction of inhibitory and emotional processes that recruits brain regions beyond those engaged by either processes alone. In this study, we isolated brain activity associated with response inhibition and emotional processing in 24 healthy adults using event‐related functional magnetic resonance imaging (fMRI) and a go/no‐go task that independently manipulated the context preceding no‐go trials (ie, number of go trials) and the valence (ie, happy, sad, and neutral) of the face stimuli used as trial cues. Parallel quadratic trends were seen in correct inhibitions on no‐go trials preceded by increasing numbers of go trials and associated activation for correct no‐go trials in inferior frontal gyrus pars opercularis, pars triangularis, and pars orbitalis, temporoparietal junction, superior parietal lobule, and temporal sensory association cortices. Conversely, the comparison of happy versus neutral faces and sad versus neutral faces revealed valence‐dependent activation in the amygdala, anterior insula cortex, and posterior midcingulate cortex. Further, an interaction between inhibition and emotion was seen in valence‐dependent variations in the quadratic trend in no‐go activation in the right inferior frontal gyrus and left posterior insula cortex. These results suggest that the inhibition of response to emotional cues involves the interaction of partly dissociable limbic and frontoparietal networks that encode emotional cues and use these cues to exert inhibitory control over the motor, attention, and sensory functions needed to perform the task, respectively. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Why don’t you feel how I feel? Insight into the absence of empathy after severe Traumatic Brain Injury

Although the existence of empathy deficits in people with traumatic brain injury (TBI) is generally well accepted, it has been a topic of limited investigation. The current study examined the relationship between self-reported emotional and cognitive empathy and psychophysiological responding to emotionally evocative pictures in 20 patients with severe TBI and 22 control participants. Eighteen pictures with alternating pleasant, unpleasant and neutral content selected from the International Affective Picture System (IAPS) were presented whilst facial muscle responses, skin conductance, and valence and arousal ratings were measured. Self-reported emotional and cognitive empathy questionnaires were also administered. In comparison to control participants, those in the TBI group displayed a reduction in the ability to empathize both emotionally and cognitively, and evidence that these two aspects of empathy may be interconnected was established. Further, TBI participants showed reduced facial responding to unpleasant pictures, while also rating them as less unpleasant and arousing than controls. In addition, they exhibited lowered autonomic arousal to all pictures, regardless of affective valence. Interestingly, hypoarousal to pleasant pictures in particular was found to be related to the absence of empathy observed after TBI, and is consistent with the view that impaired emotional responsivity is associated with impairment to the empathy network. The results represent a further step towards understanding what processes shape empathy.