Sabine M. Grüsser

Effect of sensory discrimination training on cortical reorganisation and phantom limb pain

Phantom limb pain is a frequent consequence of the amputation of a body part. Based on the finding that phantom limb pain is closely associated with plastic changes in the primary somatosensory cortex and animal data showing that behaviourally relevant training alters the cortical map, we devised a sensory discrimination training programme for patients with intractable phantom limb pain. Compared with a control group of medically treated patients, the training group had significant reductions in phantom limb pain (p=0.002) and cortical reorganisation (p=0.05) that were positively associated with improved sensory discrimination ability.

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.

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.

Alcohol-associated stimuli activate the ventral striatum in abstinent alcoholics.

Summary. Alcohol-associated cues may act as conditioned stimuli that activate the brain reward system and motivate alcohol intake in alcoholics. Alcohol-associated visual stimuli were presented during functional magnetic resonance imaging. An activation of the ventral putamen was observed in alcoholics but not in control subjects. Patients with a strong activation of the ventral putamen relapsed during the next three months. This observation supports the hypothesis that alcohol use affects areas involved in brain reward circuits and that their stimulus-induced activation may be associated with an increased risk for relapse.

Development of alcohol-associated cues and cue-induced brain activation in alcoholics

The objective of this study was to develop new standardized alcohol-associated cues and assess their effects on brain activation with functional magnetic resonance imaging (fMRI). Pictures of alcoholic and neutral beverages and affectively neutral pictures were presented to 44 abstinent alcoholics and 37 age-matched healthy control subjects. We assessed the skin conductance response, and the elicited arousal and valence. Alcoholics and control subjects did not differ in arousal, valence or skin conductance response evoked by alcohol-associated and affectively neutral stimuli, while nonalcoholic beverages were rated as more unpleasant and arousing by alcoholics compared with control subjects. In the fMRI pilot study, alcohol and abstract pictures were presented to six abstinent alcoholics and induced a significant activation of brain areas associated with visual emotional processes such as the fusiform gyrus, parts of the brain reward system (basal ganglia and orbitofrontal gyrus) and further brain regions in the frontal and parietal cortices associated with the attention network. These observations suggest that standardized pictures of alcoholic beverages can be used to assess brain circuits involved in the processing and evaluation of alcohol cues.

The relationship of perceptual phenomena and cortical reorganization in upper extremity amputees

In this study 16 unilateral upper extremity amputees participated in a comprehensive psychophysiological examination that included the assessment of painful and non-painful phantom and stump sensations, thermal and electric perception as well as two-point discrimination thresholds, the detailed analysis of referred sensation and the measurement of reorganizational changes in primary somatosensory cortex using neuroelectric source imaging. Reorganization of the primary somatosensory cortex was associated with increased habitual phantom limb pain, telescoping, non-painful stump sensations and painful referred sensation induced by painful stimulation. It was unrelated to non-painful phantom sensations, non-painful referred sensation elicited by painful or non-painful stimulation, painful referred sensation elicited by non-painful stimulation, perception thresholds and stump pain. These data substantiate the hypothesis that painful and non-painful phantom phenomena are mediated by different neural substrates.

Specific cue reactivity on computer game-related cues in excessive gamers.

It has been posited that excessive computer game playing behavior, referred to as computer game addiction, meets criteria that have been internationally established to define drug addiction. Nevertheless, there have been no psychophysiological investigations of the underlying mechanisms available to support the characterization of excessive computer gaming as behavioral addiction. To investigate whether excessive computer gaming parallels learning processes in development and maintenance (which are assumed to underlie drug addiction), the authors obtained a psychophysiological assessment of the (learned) emotional processing of computer game-relevant and -irrelevant cues. For this purpose, electroencephalographic recordings in excessive and casual computer game players were conducted. Significant between-group differences in event-related potentials evoked by computer game related-cues were found at parietal regions and point to an increased emotional processing of these cues in excessive pathological players compared with casual players. These results are in concordance with the suggestion that addiction is characterized and maintained through sensitization of the mesolimbic dopaminergic system along with incentive salience of specific addiction-associated cues.

Standardized stimuli to assess drug craving and drug memory in addicts

Summary. Due to conditioning processes, originally neutral stimuli become drug-associated cues and can initiate drug craving. Standardized stimuli are required to assess stimulus-induced activation of drug memory and craving in brain imaging and neurophysiology studies. We developed substance-specific visual and olfactory stimuli for alcohol, tobacco, opiate and cannabis abuse and tested them in subjects with the respective addiction and in healthy volunteers. Stimulus-related drug craving differed significantly between the diagnostic groups and indicated that the stimuli are suitable for craving studies.

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.

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.