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Udo Dannlowski, Harald Kugel, Franziska Huber, Anja Stuhrmann, Ronny Redlich, Dominik Grotegerd, Katharina Dohm, Christina Sehlmeyer, Carsten Konrad, Bernhard T. Baune, Volker Arolt, Walter Heindel, Pienie Zwitserlood and Thomas Suslow

The functional catechol-O-methyltransferase (COMT) val158met polymorphism has been found to be associated with anxiety disorders and depression as well as with neural correlates of emotional processing, with, however, contradictory results. Thus, the aim of the present study was to re-evaluate the impact of the COMT val158met variant on neural activation correlates of emotional face processing in a sample of healthy probands. In 85 healthy subjects genotyped for the COMT val158met polymorphism, amygdala responses were assessed by means of fMRI. Participants were presented with anger- and fear-relevant faces in a robust emotion-processing paradigm. For exploratory reasons, a supplementary whole-brain analysis of the allele-dose model and a gender-stratified analysis were conducted. The COMT 158val allele showed an allele-dose effect on increased predominantly left-sided amygdala activity in response to fearful/angry facial stimuli (p(uncorrected)=.00004). This effect was independent from the distribution of the frequently studied 5-HTTLPR polymorphism for which a linear effect of S-alleles on amygdala responsiveness was replicated. The influence of COMT 158val alleles was only discerned in the female subgroup of probands. The whole-brain analysis suggested associations of the COMT 158val allele with increased activity in areas of the ventral visual stream and the lateral prefrontal cortex. The present results provide further support for a-potentially female-specific-role of the COMT val158met polymorphism in the genetic and neural underpinnings of anxiety- and depression-related intermediate phenotypes and may aid in further clarifying the differential role of COMT genotype driven dopaminergic tonus in the processing of emotionally salient stimuli.

The hemispheres of the human brain are functionally asymmetric. The left hemisphere tends to be dominant for language and superior in the control of manual dexterity. The mechanisms underlying these asymmetries are not known. Genetic as well as environmental factors are discussed. Recently, atypical anticlockwise hair-whorl direction has been related to an increased probability for non-right-handedness and atypical hemispheric language dominance. These findings are fascinating and important since hair-whorl direction is a structural marker of lateralization and could provide a readily observable anatomical clue to functional brain lateralization. Based on data on handedness and hair-whorl direction, Amar Klar proposed a genetic model ("random-recessive model") in that a single gene with two alleles controls both handedness and hair-whorl orientation (Klar, A.J.S., 2003. Human handedness and scalp hair-whorl direction develop from a common genetic mechanism. Genetics 165, 269-276). The present study was designed to further investigate the relationship between scalp hair-whorl direction with handedness and hemispheric language dominance. 1212 subjects were investigated for scalp hair-whorl direction and handedness. Additionally, we determined hemispheric language dominance (as assessed by a word generation task) in a subgroup of 212 subjects using functional transcranial Doppler sonography (fTCD). As for the single attributes - hair-whorl direction, handedness, and language dominance - we reproduced previously published results. However, we found no association between hair-whorl direction and either language dominance or handedness. These results strongly argue against a common genetic basis of handedness or language lateralization with scalp hair-whorl direction. Inspection of hair patterns will not help us to determine language dominance.

Major depression has been repeatedly associated with amygdala hyper‐responsiveness to negative (but not positive) facial expressions at early, automatic stages of emotion processing using subliminally presented stimuli. However, it is not clear whether this “limbic bias” is a correlate of depression or represents a vulnerability marker preceding the onset of the disease. Because childhood maltreatment is a potent risk factor for the development of major depression in later life, we explored whether childhood maltreatment is associated with amygdalar emotion processing bias in maltreated but healthy subjects. Amygdala responsiveness to subliminally presented sad and happy faces was measured by means of fMRI at 3 T in N = 150 healthy subjects carefully screened for psychiatric disorders. Childhood maltreatment was assessed by the 25‐item childhood trauma questionnaire (CTQ). A strong association of CTQ‐scores with amygdala responsiveness to sad, but not happy facial expressions emerged. This result was further qualified by an interaction of emotional valence and CTQ‐scores and was not confounded by trait anxiety, current depression level, age, gender, intelligence, education level, and more recent stressful life‐events. Childhood maltreatment is apparently associated with detectable changes in amygdala function during early stages of emotion processing which resemble findings described in major depression. Limbic hyper‐responsiveness to negative facial cues could be a consequence of the experience of maltreatment during childhood increasing the risk of depression in later life. Limitation: the present association of limbic bias and maltreatment was demonstrated in the absence of psychopathological abnormalities, thereby limiting strong conclusions. Hum Brain Mapp 34:2899–2909, 2013. © 2012 Wiley Periodicals, Inc.

BackgroundFear conditioning involves the amygdala as the main neural structure for learning fear responses whereas fear extinction mainly activates the inhibitory prefrontal cortex (PFC). In this study we investigated whether individual differences in trait anxiety affect amygdala and dorsal anterior cingulate cortex (dACC) activation during fear conditioning and extinction.MethodThirty-two healthy subjects were investigated by functional magnetic resonance imaging (fMRI) at 3 T while performing a cued fear-conditioning task. All participants completed the trait version of the State-Trait Anxiety Inventory (STAI-T). Activations of the amygdala and the dACC were examined with respect to the effects of trait anxiety.ResultsAnalysis of the fMRI data demonstrated enhanced activation in fear-related brain areas, such as the insula and the ACC, during both fear conditioning and extinction. Activation of the amygdala appeared only during the late acquisition phase whereas deactivation was observed during extinction. Regression analyses revealed that highly trait-anxious subjects exhibited sustained amygdala activation and reduced dACC involvement during the extinction of conditioned responses.ConclusionsThis study reveals that high levels of trait anxiety are associated with both increased amygdala activation and reduced dACC recruitment during the extinction of conditioned fear. This hyper-responsitivity of the amygdala and the deficient cognitive control during the extinction of conditioned fear in anxious subjects reflect an increased resistance to extinct fear responses and may thereby enhance the vulnerability to developing anxiety disorders.

Executive functions such as set-shifting and maintenance are cognitive processes that rely on complex neurodevelopmental processes. Although neurodevelopmental processes are mainly studied in animal models and in neuropsychiatric disorders, the underlying genetic basis for these processes under physiological conditions is poorly understood. We aimed to investigate the association between genetic variants of the Reelin (RELN) gene and cognitive set-shifting in healthy young individuals. The relationship between 12 selected single nucleotide polymorphisms (SNPs) of the RELN gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N = 98 young healthy individuals (mean age in years: 22.7 ± 0.19). Results show that in individual MANCOVA analyses two of five significant SNPs (rs2711870: F 2,39 = 7.14; p = 0.0019; rs2249372: F 2,39 = 6.97; p = 0.002) withstood Bonferroni correction for multiple testing (corrected p -value: p = 0.004). While haplotype analyses of the RELN gene showed significant associations between three haplotypes and perseverative error processing in various models of inheritance (adjusted for age, gender, BDI, MWTB IQ), the GCT haplotye showed the most robust finding with a recessive model of inheritance ( p = 2.32 × 10 −5 ) involving the functional SNP rs362691 (Leu-Val amino acid change). Although our study strongly suggests the involvement of the RELN gene in cognitive set-shifting and maintenance, our study requires further exploration as well as replication of the findings in larger samples of healthy individuals and in clinical samples with neuropsychiatric disorders.

Set-shifting and maintenance are complex cognitive processes, which are often impaired in schizophrenia. The genetic basis of these processes is poorly understood. We aimed to investigate the association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set-shifting in healthy individuals. The relationship between 14 selected single nucleotide polymorphisms (SNPs) of the GRM3 gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N = 98 young healthy individuals (mean age in years: 22.7 +/- 0.19). Results show that SNP rs17676277 is related to the performance on the MCST. Subjects with the TT genotype showed significantly less perseverative errors as compared with the AA (P = 0.025) and AT (P = 0.0005) and combined AA/AT genotypes (P = 0.0005). Haplotype analyses suggest the involvement of various SNPs of the GRM3 gene in perseverative error processing in a dominant model of inheritance. The findings strongly suggest that the genetic variation (rs17676277 and three haplotypes) in the metabotropic GRM3 is related to cognitive set-shifting in healthy individuals independent of working memory. However, because of a relatively small sample size for a genetic association study, the present results are tentative and require replication.

Anxiety is often associated with impaired cognitive control and avoidance behaviour. The aim of this study was to investigate the effect of anxiety-related personality traits, such as anxiety sensitivity and trait anxiety, on event-related potentials of response inhibition in a standard Go/Nogo-paradigm. We focused on the Nogo-N2 and Nogo-P3 components, which probably represent different sub-processes of response inhibition. The Nogo-N2 was mainly influenced by trait anxiety, while it was slightly affected by anxiety sensitivity. In contrast, the Nogo-P3 was significantly associated with anxiety sensitivity, but was less affected by trait anxiety. Thus, anxious subjects seem to maintain a higher level of cognitive control to prepare and to monitor the outcome of their actions, which is differentially reflected in Nogo-N2 and Nogo-P3 potentials. Our results show that anxiety-related personality traits modulate electrophysiological responses related to cognitive control processes and should be taken into consideration in studies investigating response inhibition.

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.

Objectives The medial temporal lobe (MTL) is essential for declarative memory formation, but also a frequent source of seizures. To decrease the risk of amnestic impairments after temporal lobectomy, functional magnetic resonance imaging (fMRI) is increasingly used to establish pre-operative measures for a prognosis of postoperative memory performance. The present study addresses one of the major challenges in clinical fMRI, the interpretation of activation pattern in single subjects. Before investigating patients however, it must be first assessed to which extent the verbal memory paradigm can be used to determine the lateralization and the functional neuroanatomy of MTL-activity. Therefore, this study took a “step backwards” by first examining healthy subjects without known MTL pathology. Patients and methods An implicit verbal encoding task was applied to a group of ten healthy volunteers using fMRI. Results At the group level the MTL activation was strongly left-lateralized and separated into three distinct clusters. At the individual level, the lateralization of MTL-activity could be determined in 9 of 10 subjects. In contrast, its localization was inter-individually highly variable. In each case, only one of the three group activation clusters was detected. Conclusions The present study shows that fMRI can be used to assess the lateralization of brain activity related to verbal encoding even in individual subjects. For the routine use in a clinical setting however, the results of verbal memory paradigms must at present be treated with care if they are used to support decisions as to how far the resection of one MTL can be extended.

The hemispheres of the human brain are functionally asymmetric. The left hemisphere tends to be dominant for language and superior in the control of manual dexterity. The mechanisms underlying these asymmetries are not known. Genetic as well as environmental factors are discussed. Recently, atypical anticlockwise hair-whorl direction has been related to an increased probability for non-right-handedness and atypical hemispheric language dominance. These findings are fascinating and important since hair-whorl direction is a structural marker of lateralization and could provide a readily observable anatomical clue to functional brain lateralization. Based on data on handedness and hair-whorl direction, Amar Klar proposed a genetic model ("random-recessive model") in that a single gene with two alleles controls both handedness and hair-whorl orientation (Klar, A.J.S., 2003. Human handedness and scalp hair-whorl direction develop from a common genetic mechanism. Genetics 165, 269-276). The present study was designed to further investigate the relationship between scalp hair-whorl direction with handedness and hemispheric language dominance. 1212 subjects were investigated for scalp hair-whorl direction and handedness. Additionally, we determined hemispheric language dominance (as assessed by a word generation task) in a subgroup of 212 subjects using functional transcranial Doppler sonography (fTCD). As for the single attributes - hair-whorl direction, handedness, and language dominance - we reproduced previously published results. However, we found no association between hair-whorl direction and either language dominance or handedness. These results strongly argue against a common genetic basis of handedness or language lateralization with scalp hair-whorl direction. Inspection of hair patterns will not help us to determine language dominance.