Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approachinvestigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (po0.001, Cohen's d ¼ 0.535), (2) increased SPS and SIAS scores (po0.001), (3) increased cortisol response to the TSST (p ¼ 0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p corr o0.001; left: p corr ¼ 0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system.

Diffusion tensor imaging revealed that trait anxiety predicts the microstructural properties of a prespecified fiber tract between the amygdala and the perigenual anterior cingulate cortex. Besides this particular pathway, it is likely that other pathways are also affected. We investigated white matter differences in persons featuring an anxious or a nonanxious personality, taking into account all potential pathway connections between amygdala and anxiety-related regions of the prefrontal cortex (PFC). Diffusion-weighted images, measures of trait anxiety and of reappraisal use (an effective emotion-regulation style), were collected in 48 females. With probabilistic tractography, pathways between the amygdala and the dorsolateral PFC, dorsomedial PFC, ventromedial PFC, and orbitofrontal cortex (OFC) were delineated. The resulting network showed a direct ventral connection between amygdala and PFC and a second limbic connection following the fornix and the anterior limb of the internal capsule. Reappraisal use predicted the microstructure of pathways to all calculated PFC regions in the left hemisphere, indicating stronger pathways for persons with high reappraisal use. Trait anxiety predicted the microstructure in pathways to the ventromedial PFC and OFC, indexing weaker connections in trait-anxious persons. These effects appeared in the right hemisphere, supporting lateralization and top-down inhibition theories of emotion processing. Whereas a specific microstructure is associated with an anxious personality, a different structure subserves emotion regulation. Both are part of a broad fiber tract network between amygdala and PFC.

Emotional words--as symbols for biologically relevant concepts--are preferentially processed in brain regions including the visual cortex, frontal and parietal regions, and a corticolimbic circuit including the amygdala. Some of the brain structures found in functional magnetic resonance imaging are not readily apparent in electro- and magnetoencephalographic (EEG; MEG) measures. By means of a combined EEG/MEG source localization procedure to fully exploit the available information, we sought to reduce these discrepancies and gain a better understanding of spatiotemporal brain dynamics underlying emotional-word processing. Eighteen participants read high-arousing positive and negative, and low-arousing neutral nouns, while EEG and MEG were recorded simultaneously. Combined current-density reconstructions (L2-minimum norm least squares) for two early emotion-sensitive time intervals, the P1 (80-120 ms) and the early posterior negativity (EPN, 200-300 ms), were computed using realistic individual head models with a cortical constraint. The P1 time window uncovered an emotion effect peaking in the left middle temporal gyrus. In the EPN time window, processing of emotional words was associated with enhanced activity encompassing parietal and occipital areas, and posterior limbic structures. We suggest that lexical access, being underway within 100 ms, is speeded and/or favored for emotional words, possibly on the basis of an "emotional tagging" of the word form during acquisition. This gives rise to their differential processing in the EPN time window. The EPN, as an index of natural selective attention, appears to reflect an elaborate interplay of distributed structures, related to cognitive functions, such as memory, attention, and evaluation of emotional stimuli.

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Objectives. Neurobiologically, panic disorder (PD) is supposed to be characterised by cerebral hypofrontality. Via functional near-infrared spectroscopy (fNIRS), we investigated whether prefrontal hypoactivity during cognitive tasks in PD-patients compared to healthy controls (HC) could be replicated. As intermittent theta burst stimulation (iTBS) modulates cortical activity, we furthermore investigated its ability to normalise prefrontal activation. Methods. Forty-four PD-patients, randomised to sham or verum group, received 15 iTBS-sessions above the left dorsolateral prefrontal cortex (DLPFC) in addition to psychoeducation. Before first and after last iTBS-treatment, cortical activity during a verbal fluency task was assessed via fNIRS and compared to the results of 23 HC. Results. At baseline, PD-patients showed hypofrontality including the DLPFC, which differed significantly from activation patterns of HC. However, verum iTBS did not augment prefrontal fNIRS activation. Solely after sham iTBS, a significant increase of measured fNIRS activation in the left inferior frontal gyrus (IFG) during the phonological task was found. Conclusion. Our results support findings that PD is characterised by prefrontal hypoactivation during cognitive performance. However, verum iTBS as an “add-on” to psychoeducation did not augment prefrontal activity. Instead we only found increased fNIRS activation in the left IFG after sham iTBS application. Possible reasons including task-related psychophysiological arousal are discussed.