Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating.

Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥ 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.

Neural activation during anticipation of opposite-sex and same-sex faces in heterosexual men and women.

Psychobiological accounts of face processing predict that greater salience is attributed to faces matching a viewer's sexual preference than to faces that do not. However, behaviorally, this effect could only be demonstrated in tasks assessing reward 'wanting' (e.g. work-per-view-tasks) but not in tasks assessing 'liking' (e.g. facial attractiveness ratings), and has been found to be more pronounced in heterosexual men than women, especially with regard to very attractive faces. Here, we addressed the question if sex differences at the level of 'wanting' persist if participants are uninformed about the attractiveness of an anticipated male or female face. Seventeen heterosexual men and 13 heterosexual women (all single) participated in a social incentive delay task (SID). Participants were required to react on simple graphical cues in order to view a smiling face. Cues provided a priori information on the level of smile intensity (low/medium/high) as well as sex of the face (male/ female). A significant interaction of sex-of-face and sex-of-participant was observed in a priori defined regions of interest in the brain reward system (including ventral tegmental area, nucleus accumbens and ventromedial prefrontal cortex), reflecting enhanced activation to cues signaling opposite-sex faces relative to same-sex faces in both, men and women. Women additionally recruited the temporo-parietal junction (TPJ) during processing of opposite- vs. same-sex cues, suggesting stronger incorporation of social cognition processes in women than men. The findings speak against a general male bias for opposite-sex faces. Instead they provide preliminary evidence that men and women recruit different brain circuits during reward value assessment of facial stimuli.

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.

Psychological and hormonal features of smokers at risk to gain weight after smoking cessation--results of a multicenter study.

Preclinical and clinical data suggest modulating effects of appetite-regulating hormones and stress perception on food intake. Nicotine intake also interferes with regulation of body weight. Especially following smoking cessation gaining weight is a common but only partially understood consequence. The aim of this study was to examine the interaction between smoking habits, the appetite regulating hormone leptin, negative affectivity, and stress vulnerability on eating behavior in a clinical case-control study under standardized conditions. In a large population-based study sample, we compared leptin and cortisol plasma concentrations (radioimmunoassay) between current tobacco smokers with high cognitive restraint and disinhibition in eating behavior and smokers scoring low in both categories as assessed with the Three Factor Eating Questionnaire (TFEQ; Stunkard & Messick, 1985). As a measure for smoking effects on the stress axis, the saliva cortisol concentrations were compared before and after nicotine smoking. Additionally, stress perception was assessed with the Perceived Stress Scale (PSS), symptoms of depression and anxiety with the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI). In smokers showing high cognitive restraint and disinhibition we found significantly higher leptin concentrations than in the group of smokers scoring low in both categories. Furthermore there was a significant group difference in saliva cortisol concentrations after nicotine intake. Smokers showing high cognitive restraint and disinhibition were also characterized by significantly higher scores in the STAI, the PSS and the BDI. Our results suggest that smokers with a pathological eating behavior show an impaired neuroendocrine regulation of appetite and are prone to experience higher levels of stress and negative affectivity. This interaction of behavioral and neuroendocrinological factors may constitute a high risk condition for gaining weight following smoking cessation.

P50 sensory gating and smoking in the general population.

P50 gating is a major functional biomarker in research on schizophrenia and other psychiatric conditions with high smoking prevalence. It is used as endophenotype for studying nicotinic systems genetics and as surrogate endpoint measure for drug development of nicotinic agonists. Surprisingly, little is known about P50 gating in the general population and the relationship to smoking-related characteristics. In this multicenter study at six academic institutions throughout Germany, n=907 never-smokers (NS<20 cigarettes/lifetime), n=463 light smokers (LS) with Fagerström Test for Nicotine Dependence (FTND)≥4 and n=353 heavy smokers (HS, FTND<4) were randomly selected from the general population. As part of a standardized protocol for investigating the genetics of nicotine dependence (ND), an auditory P50 paradigm was applied. The main outcome measure was P50-amplitude difference followed by time-frequency analyses and functional imaging (sLORETA). Reduced P50 gating was found in HS compared to NS with LS taking an intermediate position-correlating with the degree of ND. sLORETA and time-frequency analyses indicate that high-frequency oscillations in frontal brain regions are particularly affected. With growing age, P50 gating increased in (heavy) smokers. This is the first large-scale study (normative sample data) on P50 sensory gating and smoking in the general population. Diminished gating of P50 and associated high-frequency oscillations in the frontal brain region are indications of a deficient inhibitory cortical function in nicotine-dependent smokers. The suitability and application of sensory P50 gating as functional biomarker with regard to genetic and pharmacological studies is discussed.

The German multi-centre study on smoking-related behavior-description of a population-based case-control study.

Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND-related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes', which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: 'Nicotine-Molecular and Physiological Effects in CNS', was intended to overcome some of these inherent problems of current genetic studies of ND. The multi-centre study is a population-based case-control study of smokers and never-smokers (n = 2396). The study was unique worldwide because it was the first large-scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper.

Dissociation of neural networks for anticipation and consumption of monetary and social rewards.

Human behaviour is generally guided by the anticipation of potential outcomes that are considered to be rewarding. Reward processing can thus be dissected into a phase of reward anticipation and a phase of reward consumption. A number of brain structures have been suggested to be involved in reward processing. However, it is unclear whether anticipation and consumption are mediated by the same or different neural networks. We examined the neural basis of these processes using functional magnetic resonance imaging (fMRI) in an incentive delay task offering either money or social approval. In both conditions participants (N=28) were given a cue indicating potential reward. In order to receive reward a target button had to be pushed within a certain time window (adapted for individual reaction time). Cues triggering either monetary or social reward anticipation were presented sessionwise. Imaging was performed on a 1.5-Tesla Philips scanner in an event-related design. Anticipation of both reward types activated brain structures constituting the brain reward system including the ventral striatum. In contrast to the task independent activity in the anticipation phase, reward consumption evoked different patterns of activation for money and social approval, respectively. While social stimuli were mainly associated with amygdala activation, the thalamus was more strongly activated by the presentation of monetary rewards. Our results identify dissociable neural networks for the anticipation and consumption of reward. The findings implicate that the neural mechanisms underlying reward consumption are more modality-specific than those for reward anticipation, and that they are mediated by subjective reward value.

Neural processing of vocal emotion and identity.

The voice is a marker of a person's identity which allows individual recognition even if the person is not in sight. Listening to a voice also affords inferences about the speaker's emotional state. Both these types of personal information are encoded in characteristic acoustic feature patterns analyzed within the auditory cortex. In the present study 16 volunteers listened to pairs of non-verbal voice stimuli with happy or sad valence in two different task conditions while event-related brain potentials (ERPs) were recorded. In an emotion matching task, participants indicated whether the expressed emotion of a target voice was congruent or incongruent with that of a (preceding) prime voice. In an identity matching task, participants indicated whether or not the prime and target voice belonged to the same person. Effects based on emotion expressed occurred earlier than those based on voice identity. Specifically, P2 (approximately 200 ms)-amplitudes were reduced for happy voices when primed by happy voices. Identity match effects, by contrast, did not start until around 300 ms. These results show an early task-specific emotion-based influence on the early stages of auditory sensory processing.

Effects of alexithymia and empathy on the neural processing of social and monetary rewards.

Empathy has been found to affect the neural processing of social and monetary rewards. Alexithymia, a subclinical condition showing a close inverse relationship with empathy is linked to dysfunctions of socio-emotional processing in the brain. Whether alexithymia alters the neural processing of rewards, which is currently unknown. Here, we investigated the influence of both alexithymia and empathy on reward processing using a social incentive delay (SID) task and a monetary incentive delay (MID) task in 45 healthy men undergoing functional magnetic resonance imaging. Controlling for temperament-character dimensions and rejection sensitivity, the relationship of alexithymia and empathy with neural activity in several a priori regions of interest (ROIs) was examined by means of partial correlations, while participants anticipated and received social and monetary rewards. Results were considered significant if they survived Holm-Bonferroni correction for multiple comparisons. Alexithymia modulated neural activity in several ROIs of the emotion and reward network, both during the anticipation of social and monetary rewards and in response to the receipt of monetary rewards. In contrast, empathy did not affect reward anticipation and modulated ROI activity only in response to the receipt of social rewards. These results indicate a significant influence of alexithymia on the processing of social and monetary rewards in the healthy brain.

Combined perception of emotion in pictures and musical sounds.

Evaluation of emotional scenes requires integration of information from different modality channels, most frequently from audition and vision. Neither the psychological nor neural basis of auditory-visual interactions during the processing of affect is well understood. In this study, possible interactions in affective processing were investigated via event-related potential (ERP) recordings during simultaneous presentation of affective pictures (from IAPS) and affectively sung notes that either matched or mismatched each other in valence. To examine the role of attention in multisensory affect-integration ERPs were recorded in two different rating tasks (voice affect rating, picture affect rating) as participants evaluated the affect communicated in one of the modalities, while that in the other modality was ignored. Both the behavioral and ERP data revealed some, although non-identical, patterns of cross-modal influences; modulation of the ERP-component P2 suggested a relatively early integration of affective information in the attended picture condition, though only for happy picture-voice pairs. In addition, congruent pairing of sad pictures and sad voice stimuli affected the late positive potential (LPP). Responses in the voice affect rating task were overall more likely to be modulated by the concomitant picture's affective valence than vice versa.

Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample.

Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disorders. Converging lines of research in rodents and humans point towards an involvement of the nicotinic cholinergic system in the modulation of anxiety. Most notably, the rs1044396 polymorphism in the CHRNA4 gene, which codes for the α4 subunit of the nicotinic acetylcholine receptor, has been linked to negative emotionality traits including harm avoidance in a recent study. Against this background, we investigated the association between harm avoidance and the rs1044396 polymorphism using data from N=1673 healthy subjects, which were collected in the context of the German multi-centre study ׳Genetics of Nicotine Dependence and Neurobiological Phenotypes׳. Homozygous carriers of the C-allele showed significantly higher levels of harm avoidance than homozygous T-allele carriers, with heterozygous subjects exhibiting intermediate scores. The effect was neither modulated by age or gender nor by smoking status. By replicating previous findings in a large population-based sample for the first time, the present study adds to the growing evidence suggesting an involvement of nicotinic cholinergic mechanism in anxiety and negative emotionality, which may pose an effective target for medical treatment.

Differential patterns of nucleus accumbens activation during anticipation of monetary and social reward in young and older adults.

Recent studies have reported inconsistent results regarding the loss of reward sensitivity in the aging brain. Although such an age effect might be due to a decline of physiological processes, it may also be a consequence of age-related changes in motivational preference for different rewards. Here, we examined whether the age effects on neural correlates of reward anticipation are modulated by the type of expected reward. Functional magnetic resonance images were acquired in 24 older (60-78 years) and 24 young participants (20-28 years) while they performed an incentive delay task offering monetary or social rewards. Anticipation of either reward type recruited brain structures associated with reward, including the nucleus accumbens (NAcc). Region of interest analysis revealed an interaction effect of reward type and age group in the right NAcc: enhanced activation to cues of social reward was detected in the older subsample while enhanced activation to cues of monetary reward was detected in the younger subsample. Our results suggest that neural sensitivity to reward-predicting cues does not generally decrease with age. Rather, neural responses in the NAcc appear to be modulated by the type of reward, presumably reflecting age-related changes in motivational value attributed to different types of reward.

Neural evidence for an association between social proficiency and sensitivity to social reward.

Data from developmental psychology suggests a link between the growth of socio-emotional competences and the infant's sensitivity to the salience of social stimuli. The aim of the present study was to find evidence for this relationship in healthy adults. Thirty-five participants were recruited based on their score above the 85th or below the 15th percentile of the empathy quotient questionnaire (EQ, Baron-Cohen and Wheelwright, 2004). Functional magnetic resonance imaging (fMRI) was used to compare neural responses to cues of social and non-social (monetary) reward. When compared to the high-EQ group, the low-EQ group showed reduced activity of the brain s reward system, specifically the right nucleus accumbens, in response to cues predictive of social reward (videos showing gestures of approval)-but increased activation in this area for monetary incentives. Our data provide evidence for a link between self-reported deficits in social proficiency and reduced sensitivity to the motivational salience of positive social stimuli.

Preattentive processing of emotional musical tones: a multidimensional scaling and ERP study.

Musical emotion can be conveyed by subtle variations in timbre. Here, we investigated whether the brain is capable to discriminate tones differing in emotional expression by recording event-related potentials (ERPs) in an oddball paradigm under preattentive listening conditions. First, using multidimensional Fechnerian scaling, pairs of violin tones played with a happy or sad intonation were rated same or different by a group of non-musicians. Three happy and three sad tones were selected for the ERP experiment. The Fechnerian distances between tones within an emotion were in the same range as the distances between tones of different emotions. In two conditions, either 3 happy and 1 sad or 3 sad and 1 happy tone were presented in pseudo-random order. A mismatch negativity for the emotional deviant was observed, indicating that in spite of considerable perceptual differences between the three equiprobable tones of the standard emotion, a template was formed based on timbral cues against which the emotional deviant was compared. Based on Juslin's assumption of redundant code usage, we propose that tones were grouped together, because they were identified as belonging to one emotional category based on different emotion-specific cues. These results indicate that the brain forms an emotional memory trace at a preattentive level and thus, extends previous investigations in which emotional deviance was confounded with physical dissimilarity. Differences between sad and happy tones were observed which might be due to the fact that the happy emotion is mostly communicated by suprasegmental features.

Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain.

BACKGROUND: Evidence accumulates that the neuropeptide oxytocin plays an important role in mediating social interaction among humans and that a dysfunction in oxytocin-modulated brain mechanisms might lie at the core of disturbed social behavior in neuropsychiatric disease. Explanatory models suggest that oxytocin guides social approach and avoidance by modulating the perceived salience of socially meaningful cues. Animal data point toward the ventral tegmental area (VTA) as the brain site where this modulation takes place. METHODS: We used functional magnetic resonance imaging and a social incentive delay task to test the hypothesis that oxytocin modulates the neural processing of socially relevant cues in the VTA, hereby facilitating behavioral response. Twenty-eight nulliparous women (not taking any hormones) received intranasal oxytocin or placebo in a double-blind randomized clinical trial with a parallel-group design. RESULTS: Oxytocin significantly enhanced VTA activation in response to cues signaling social reward (friendly face) or social punishment (angry face). Oxytocin effects on behavioral performance were modulated by individual differences in sociability with enhanced performance in women scoring low but decreased performance in women scoring high on self-reported measures of agreeableness. CONCLUSIONS: Our data provide evidence that the VTA is the human brain site where oxytocin attaches salience to socially relevant cues. This mechanism might play an important role in triggering motivation to react at the prospect of social reward or punishment.

Emotional and analytic music perception in cochlear implant users after optimizing the speech processor.

CONCLUSION: Cochlear implant (CI) users are able to detect harmonic differences and the emotionally exciting effect of music (arousal) even when using a speech adapted program. Raising the power of lower frequencies of speech processors in CIs for a music program further improved this ability and enhanced subjectively perceived pleasure during listening to music. OBJECTIVE: This pilot study compares aspects of analytical and emotional music perception before and after optimizing the speech processor compared to results of normal-hearing subjects. METHODS: Six adult post-lingually deafened CI users and six subjects with normal hearing abilities were tested on different aspects of analytical and emotional music perception. After optimizing speech processors for a music program, the CI users were tested again after a period of 1 week. RESULTS: The CI users were able to detect different levels of emotional arousal conveyed by music. Switching to the music program resulted in an even better distinction between different levels of musical arousal. With both the speech and music programs, CI users gave overall higher ratings for arousal and valence of the heard music when asked to estimate how listeners with normal hearing perceived the music than when asked about their own perception.

Opiate-induced dopamine release is modulated by severity of alcohol dependence: an [(18)F]fallypride positron emission tomography study.

BACKGROUND: Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of ß-endorphins stimulates µ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the ß-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. METHODS: Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). RESULTS: The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. CONCLUSIONS: The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found.

Anticipation of monetary and social reward differently activates mesolimbic brain structures in men and women.

Motivation for goal-directed behaviour largely depends on the expected value of the anticipated reward. The aim of the present study was to examine how different levels of reward value are coded in the brain for two common forms of human reward: money and social approval. To account for gender differences 16 male and 16 female participants performed an incentive delay task expecting to win either money or positive social feedback. fMRI recording during the anticipation phase revealed proportional activation of neural structures constituting the human reward system for increasing levels of reward, independent of incentive type. However, in men activation in the prospect of monetary rewards encompassed a wide network of mesolimbic brain regions compared to only limited activation for social rewards. In contrast, in women, anticipation of either incentive type activated identical brain regions. Our findings represent an important step towards a better understanding of motivated behaviour by taking into account individual differences in reward valuation.