The production of chemokines by astrocytes constitutes an important component of neuroinflammatory processes in the brain. As the transcriptional activator retinoic acid (RA), used for chemotherapy and dermatological applications, exerts anti-inflammatory effects on monocytes and lymphocytes, we have tested whether the physiologically occurring isomer, alltrans RA, affects chemokine expression by astrocytes. Under control conditions, primary cultures of murine cortical astrocytes expressed no or very low levels of CCL and CXCL chemokines. After treatment with bacterial lipopolysaccharides to simulate inflammation in vitro, we detected a strong increase in the release of CCL2 (to > 4 ng/mL in cell culture supernatant), CCL3 (> 20 ng/mL), CCL5 (> 25 ng/mL), CXCL1 (> 30 ng/mL) and CXCL2 (> 20 ng/mL). Although simultaneous exposure to RA did not significantly affect this response, 12 h pre-treatment with 0.1 lM all-trans RA strongly suppressed mRNA expression and protein release of all chemokines. The anti-inflammatory activity of RA engaged RA and retinoid X receptors and correlated with a decreased expression of the lipopolysaccharides co-receptor CD14. A minor reduction of nuclear NF-jB was observed but not significant, activation of Jun amino-terminal kinase, p38 and signal transducer and activator of transcription 3 were not altered by RA. The results suggest that retinoids should be further investigated as candidates for the treatment of neuroinflammation.

Disruptions in the cortico-limbic emotion regulation networks have been linked to depression, anxiety, impulsivity, and aggression. Altered transmission of the central nervous serotonin (5-HT) contributes to dysfunctions in the cognitive control of emotions. To date, studies relating to pharmaco-fMRI challenging of the 5-HT system have focused on emotion processing for facial expressions. We investigated effects of a single-dose selective 5-HT reuptake inhibitor (escitalopram) on emotion regulation during virtual violence. For this purpose, 38 male participants played a violent video game during fMRI scanning. The SSRI reduced neural responses to violent actions in right-hemispheric inferior frontal gyrus and medial prefrontal cortex encompassing the anterior cingulate cortex (ACC), but not to non-violent actions. Within the ACC, the drug effect differentiated areas with high inhibitory 5-HT1A receptor density (subgenual s25) from those with a lower density (pregenual p32, p24). This finding links functional responses during virtual violent actions with 5-HT neurotransmission in emotion regulation networks, underpinning the ecological validity of the 5-HT model in aggressive behavior. Available 5-HT receptor density data suggest that this SSRI effect is only observable when inhibitory and excitatory 5-HT receptors are balanced. The observed early functional changes may impact patient groups receiving SSRI treatment.

MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc.

Aggressive behavior is associated with dysfunctional frontolimbic emotion regulation circuits. Recent findings suggest serotonin as a primary transmitter for prefrontal amygdala control. However, the association between serotonin levels, amygdala regulation, and aggression is still a matter of debate. Neurobehavioral models furthermore suggest a possible mediating influence of the monoamine oxidase A gene ( MAOA ) on this brain-behavior relationship, with carriers of low expressing allele varieties being a risk group for aggression. In the present study, we investigated the influence of brain serotonin modulation and MAOA genotype on functional amygdala connectivity during aggressive behavior. Modulation of serotonergic neurotransmission with acute tryptophan depletion (ATD) and placebo were administered in a double-blind, cross-over design in 38 healthy male participants. Aggressive behavior was modeled in a violent video game during simultaneous assessment of brain activation with functional magnetic resonance imaging (fMRI). Trait aggression was measured with the Buss-Perry Aggression Questionnaire (BP-AQ), and MAOA genotypes were assessed from blood samples. Voxel-wise functional connectivity with anatomically defined amygdala was calculated from the functional data. Tryptophan depletion with ATD reduced aggression-specific amygdala connectivity with bilateral supramarginal gyrus. Moreover, ATD impact was associated with trait aggression and MAOA genotype in prefrontal cortex regions. In summary, serotonergic corticolimbic projections contribute to aggressive behavior. Genotype-specific vulnerability of frontolimbic projections may underlie the elevated risk in low expressing allele carriers.

Low expressing alleles of the MAOA gene (MAOA-L) have been associated with an increased risk for developing an aggressive personality. This suggests an MAOA-L-specific neurobiological vulnerability associated with trait aggression. The neural networks underlying this vulnerability are unknown. The present study investigated genotype-specific associations between resting state brain networks and trait aggression (Buss-Perry Aggression Questionnaire) in 82 healthy Caucasian males. Genotype influences on aggression-related networks were studied for intrinsic and seed-based brain connectivity. Intrinsic connectivity was higher in the ventromedial prefrontal cortex (VMPFC) of MAOA-L compared to high expressing allele (MAOA-H) carriers. Seed-based connectivity analyses revealed genotype differences in the functional involvement of this region. MAOA genotype modulated the relationship between trait aggression and VMPFC connectivity with supramarginal gyrus (SMG) and areas of the default mode network (DMN). Separate analyses for the two groups were performed to better understand how the genotype modulated the relationship between aggression and brain networks. They revealed a positive correlation between VMPFC connectivity and aggression in right angular gyrus (AG) and a negative correlation in right SMG in the MAOA-L group. No such effect emerged in the MAOA-H carriers. The results indicate a particular relevance of VMPFC for aggression in MAOA-L carriers; in specific, a detachment from the DMN along with a strengthened coupling to the AG seems to go along with lower trait aggression. MAOA-L carriers may thus depend on a synchronization of emotion regulation systems (VMPFC) with core areas of empathy (SMG) to prevent aggression.

Combined EEG-fMRI analysis correlates time courses from single electrodes or independent EEG components with the hemodynamic response. Implementing information from only one electrode, however, may miss relevant information from complex electrophysiological networks. Component based analysis, in turn, depends on a priori knowledge of the signal topography. Complex designs such as studies on multisensory integration of emotions investigate subtle differences in distributed networks based on only a few trials per condition. Thus, they require a sensitive and comprehensive approach which does not rely on a-priori knowledge about the underlying neural processes. In this pilot study, feasibility and sensitivity of source localization-driven analysis for EEG-fMRI was tested using a multisensory integration paradigm. Dynamic audiovisual stimuli consisting of emotional talking faces and pseudowords with emotional prosody were rated in a delayed response task. The trials comprised affectively congruent and incongruent displays. In addition to event-locked EEG and fMRI analyses, induced oscillatory EEG responses at estimated cortical sources and in specific temporo-spectral windows were correlated with the corresponding BOLD responses. EEG analysis showed high data quality with less than 10% trial rejection. In an early time window, alpha oscillations were suppressed in bilateral occipital cortices and fMRI analysis confirmed high data quality with reliable activation in auditory, visual and frontal areas to the presentation of multisensory stimuli. In line with previous studies, we obtained reliable correlation patterns for event locked occipital alpha suppression and BOLD signal time course. Our results suggest a valid methodological approach to investigate complex stimuli using the present source localization driven method for EEG-fMRI. This novel procedure may help to investigate combined EEG-fMRI data from novel complex paradigms with high spatial and temporal resolution.

Face-to-face communication is multimodal; it encompasses spoken words, facial expressions, gaze, and co-speech gestures. In contrast to linguistic symbols (e.g., spoken words or signs in sign language) relying on mostly explicit conventions, gestures vary in their degree of conventionality. Bodily signs may have a general accepted or conventionalized meaning (e.g., a head shake) or less so (e.g., self-grooming). We hypothesized that subjective perception of conventionality in co-speech gestures relies on the classical language network, i.e., the left hemispheric inferior frontal gyrus (IFG, Broca's area) and the posterior superior temporal gyrus (pSTG, Wernicke's area) and studied 36 subjects watching video-recorded story retellings during a behavioral and an functional magnetic resonance imaging (fMRI) experiment. It is well documented that neural correlates of such naturalistic videos emerge as intersubject covariance (ISC) in fMRI even without involving a stimulus (model-free analysis). The subjects attended either to perceived conventionality or to a control condition (any hand movements or gesture-speech relations). Such tasks modulate ISC in contributing neural structures and thus we studied ISC changes to task demands in language networks. Indeed, the conventionality task significantly increased covariance of the button press time series and neuronal synchronization in the left IFG over the comparison with other tasks. In the left IFG, synchronous activity was observed during the conventionality task only. In contrast, the left pSTG exhibited correlated activation patterns during all conditions with an increase in the conventionality task at the trend level only. Conceivably, the left IFG can be considered a core region for the processing of perceived conventionality in co-speech gestures similar to spoken language. In general, the interpretation of conventionalized signs may rely on neural mechanisms that engage during language comprehension.

Social interactions arise from patterns of communicative signs, whose perception and interpretation require a multitude of cognitive functions. The semiotic framework of Peirce’s Universal Categories (UCs) laid ground for a novel cognitive-semiotic typology of social interactions. During functional magnetic resonance imaging (fMRI), 16 volunteers watched a movie narrative encompassing verbal and non-verbal social interactions. Three types of non-verbal interactions were coded (“unresolved,” “non-habitual,” and “habitual”) based on a typology reflecting Peirce’s UCs. As expected, the auditory cortex responded to verbal interactions, but non-verbal interactions modulated temporal areas as well. Conceivably, when speech was lacking, ambiguous visual information (unresolved interactions) primed auditory processing in contrast to learned behavioral patterns (habitual interactions). The latter recruited a parahippocampal-occipital network supporting conceptual processing and associative memory retrieval. Requesting semiotic contextualization, non-habitual interactions activated visuo-spatial and contextual rule-learning areas such as the temporo-parietal junction and right lateral prefrontal cortex. In summary, the cognitive-semiotic typology reflected distinct sensory and association networks underlying the interpretation of observed non-verbal social interactions.