Frieder M. Paulus

Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity.

Background: Genome‐wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto‐hippocampal connectivity. Methods: We used functional magnetic resonance imaging to measure neural activation during an n‐back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working‐memory‐related DLPFC activation and functional integration using a seed region functional connectivity approach. Results: Rs1006737 genotype was associated with altered right‐hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G‐allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto‐hippocampal connectivity with rs1006737 A alleles. Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype‐related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. Hum Brain Mapp 35:1190–1200, 2014.

Partial support for ZNF804A genotype-dependent alterations in prefrontal connectivity.

Genome‐wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk‐variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk‐alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto‐hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems. Hum Brain Mapp, 2013.

The Rewarding Nature of Social Interactions

The objective of this short review is to highlight rewarding aspects of social interactions for humans and discuss their neural basis. Thereby we report recent research findings to illustrate how social stimuli in general are processed in the reward system and highlight the role of Theory of Mind as one mediating process for experiencing social reward during social interactions. In conclusion we discuss clinical implications for psychiatry and psychotherapy.

Test-retest reliability of dynamic causal modeling for fMRI

Dynamic causal modeling (DCM) is a Bayesian framework for inferring effective connectivity among brain regions from neuroimaging data. While the validity of DCM has been investigated in various previous studies, the reliability of DCM parameter estimates across sessions has been examined less systematically. Here, we report results of a software comparison with regard to test-retest reliability of DCM for fMRI, using a challenging scenario where complex models with many parameters were applied to relatively few data points. Specifically, we examined the reliability of different DCM implementations (in terms of the intra-class correlation coefficient, ICC) based on fMRI data from 35 human subjects performing a simple motor task in two separate sessions, one month apart. We constructed DCMs of motor regions with fair to excellent reliability of conventional activation measures. Using classical DCM (cDCM) in SPM5, we found that the test-retest reliability of DCM results was high, both concerning the model evidence (ICC=0.94) and the model parameter estimates (median ICC=0.47). However, when using a more recent DCM version (DCM10 in SPM8), test-retest reliability was reduced notably. Analyses indicated that, in our particular case, the prior distributions played a crucial role in this change in reliability across software versions. Specifically, when using cDCM priors for model inversion in DCM10, this not only restored reliability but yielded even better results than in cDCM. Analyzing each component of the objective function in DCM, we found a selective change in the reliability of posterior mean estimates. This suggests that tighter regularization afforded by cDCM priors reduces the possibility of local extrema in the objective function. We conclude this paper with an outlook to ongoing developments for overcoming the software-dependency of reliability observed in this study, including global optimization and empirical Bayesian procedures.

On the distinction of empathic and vicarious emotions

In the introduction to the special issue “The Neural Underpinnings of Vicarious Experience” the editors state that one “may feel embarrassed when witnessing another making a social faux pas”. In our commentary we address this statement and ask whether this example introduces a vicarious or an empathic form of embarrassment. We elaborate commonalities and differences between these two forms of emotional experiences and discuss their underlying mechanisms. We suggest that both, vicarious and empathic emotions, originate from the simulation processes mirroring and mentalizing that depend on anchoring and adjustment. We claim the term “empathic emotion” to be reserved exclusively for incidents where perceivers and social targets have shared affective experience, whereas “vicarious emotion” offers a wider scope and also includes non-shared affective experiences. Both are supposed to be highly functional in social interactions.

Evidence from pupillometry and fMRI indicates reduced neural response during vicarious social pain but not physical pain in autism

Autism spectrum disorder (ASD) is characterized by substantial social deficits. The notion that dysfunctions in neural circuits involved in sharing anothers affect explain these deficits is appealing, but has received only modest experimental support. Here we evaluated a complex paradigm on the vicarious social pain of embarrassment to probe social deficits in ASD as to whether it is more potent than paradigms currently in use. To do so we acquired pupillometry and fMRI in young adults with ASD and matched healthy controls. During a simple vicarious physical pain task no differences emerged between groups in behavior, pupillometry, and neural activation of the anterior insula (AIC) and anterior cingulate cortex (ACC). In contrast, processing complex vicarious social pain yielded reduced responses in ASD on all physiological measures of sharing anothers affect. The reduced activity within the AIC was thereby explained by the severity of autistic symptoms in the social and affective domain. Additionally, behavioral responses lacked correspondence with the anterior cingulate and anterior insula cortex activity found in controls. Instead, behavioral responses in ASD were associated with hippocampal activity. The observed dissociation echoes the clinical observations that deficits in ASD are most pronounced in complex social situations and simple tasks may not probe the dysfunctions in neural pathways involved in sharing affect. Our results are highly relevant because individuals with ASD may have preserved abilities to share anothers physical pain but still have problems with the vicarious representation of more complex emotions that matter in life. Hum Brain Mapp, 2015.

Neural pathways of embarrassment and their modulation by social anxiety

While being in the center of attention and exposed to others evaluations humans are prone to experience embarrassment. To characterize the neural underpinnings of such aversive moments, we induced genuine experiences of embarrassment during person-group interactions in a functional neuroimaging study. Using a mock-up scenario with three confederates, we examined how the presence of an audience affected physiological and neural responses and the reported emotional experiences of failures and achievements. The results indicated that publicity induced activations in mentalizing areas and failures led to activations in arousal processing systems. Mentalizing activity as well as attention towards the audience were increased in socially anxious participants. The converging integration of information from mentalizing areas and arousal processing systems within the ventral anterior insula and amygdala forms the neural pathways of embarrassment. Targeting these neural markers of embarrassment in the (para-)limbic system provides new perspectives for developing treatment strategies for social anxiety disorders.

Effects of ketamine-induced psychopathological symptoms on continuous overt rhyme fluency.

The N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. Administered to healthy individuals, a subanesthetic dose of the noncompetitive NMDAR antagonist ketamine reproduces several psychopathological symptoms commonly observed in patients with schizophrenia. In a counterbalanced, placebo-controlled, double-blind, within-participants study, fifteen healthy subjects were administered a continuous subanesthetic S-ketamine infusion while cortical activation was measured using functional magnetic resonance imaging. While being scanned, subjects performed an overt word generation task. Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine administration elicited effects on psychopathology, including difficulties in abstract thinking, lack of spontaneity and flow of conversation as well as formal thought disorder. On a behavioral level, verbal fluency performance was unaffected. The PANSS score for formal thought disorder positively correlated with activation measures encompassing the left superior temporal gyrus, the right middle and inferior frontal gyrus and the precuneus. Difficulty in abstract thinking was correlated with pronounced activations in prefrontal as well as in anterior cingulate regions, whereas hyperactivations in the left superior temporal gyrus were found in association with a lack of spontaneity and flow of conversation. In the absence of behavioral impairments during verbal fluency, NMDAR blocking evoked psychopathological symptoms and cortical activations in regions previously reported in schizophrenia patients. The results provide further support for the hypothesis of an NMDAR dysfunction in the pathophysiology of schizophrenia.

Journal Impact Factor Shapes Scientists’ Reward Signal in the Prospect of Publication

The incentive structure of a scientist’s life is increasingly mimicking economic principles. While intensely criticized, the journal impact factor (JIF) has taken a role as the new currency for scientists. Successful goal-directed behavior in academia thus requires knowledge about the JIF. Using functional neuroimaging we examined how the JIF, as a powerful incentive in academia, has shaped the behavior of scientists and the reward signal in the striatum. We demonstrate that the reward signal in the nucleus accumbens increases with higher JIF during the anticipation of a publication and found a positive correlation with the personal publication record (pJIF) supporting the notion that scientists have incorporated the predominant reward principle of the scientific community in their reward system. The implications of this behavioral adaptation within the ecological niche of the scientist’s habitat remain unknown, but may also have effects which were not intended by the community.

Functional Connectivity Analyses in Imaging Genetics: Considerations on Methods and Data Interpretation

Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders (“imaging genetics”). A data analysis approach that is widely applied is “functional connectivity”. In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called “seed point”) and other brain voxels is determined. In this technical note, we show how the choice of freely selectable data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters.