Negative emotionality is a well-established and stable risk factor for affective disorders. Individual differences in negative emotionality have been linked to associative learning processes which can be captured experimentally by computing CS-discrimination values in fear conditioning paradigms. Literature suffers from underpowered samples, suboptimal methods, and an isolated focus on single questionnaires and single outcome measures. First, the specific and shared variance across three commonly employed questionnaires [STAI-T, NEO-FFI-Neuroticism, Intolerance of Uncertainty (IU) Scale] in relation to CS-discrimination during fear-acquisition in multiple analysis units (ratings, skin conductance, startle) is addressed (N-Study1=356). A specific significant negative association between STAI-T and CS-discrimination in SCRs and between IU and CS-discrimination in startle responding was identified in multimodal and dimensional analyses, but also between latent factors negative emotionality and fear learning, which capture shared variance across questionnaires/scales and across outcome measures. Second, STAI-T was positively associated with CS-discrimination in a number of brain areas linked to conditioned fear (amygdala, putamen, thalamus), but not to SCRs or ratings (N-Study2=113). Importantly, we replicate potential sampling biases between fMRI and behavioral studies regarding anxiety levels. Future studies are needed to target wide sampling distributions for STAI-T and verify whether current findings are generalizable to other samples.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P =3.3 × 10 −8 ; rs191260602, P =3.9 × 10 −8 ). We followed up on this finding in a larger dimensional ACQ sample ( N =2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N =3845) and a case–control sample with the categorical phenotype PD/AG ( N combined =1012) obtaining highly significant P -values also for GLRB single-nucleotide variants rs17035816 ( P =3.8 × 10 −4 ) and rs7688285 ( P =7.6 × 10 −5 ). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Traditionally, adversity was defined as the accumulation of environmental events (allostatic load). Recently however, a mismatch between the early and the later (adult) environment (mismatch) has been hypothesized to be critical for disease development, a hypothesis that has not yet been tested explicitly in humans. We explored the impact of timing of life adversity (childhood and past year) on anxiety and depression levels (N = 833) and brain morphology (N = 129). Both remote (childhood) and proximal (recent) adversities were differentially mirrored in morphometric changes in areas critically involved in emotional processing (i.e. amygdala/hippocampus, dorsal anterior cingulate cortex, respectively). The effect of adversity on affect acted in an additive way with no evidence for interactions (mismatch). Structural equation modeling demonstrated a direct effect of adversity on morphometric estimates and anxiety/depression without evidence of brain morphology functioning as a mediator. Our results highlight that adversity manifests as pronounced changes in brain morphometric and affective temperament even though these seem to represent distinct mechanistic pathways. A major goal of future studies should be to define critical time periods for the impact of adversity and strategies for intervening to prevent or reverse the effects of adverse childhood life experiences.

The efficacy of current treatments for anxiety disorders is limited by high relapse rates. Relapse of anxiety disorders and addiction can be triggered by exposure to life adversity, but the underlying mechanisms remain unexplored. Seventy-six healthy adults were a priori selected for the presence or absence of adverse experiences during childhood (CA) and recent past (RA; that is, past 12 months). Participants underwent fear conditioning (day 1) and fear extinction and experimental return-of-fear (ROF) induction through reinstatement (a model for adversity-induced relapse; day 2). Ratings, autonomic (skin conductance response) and neuronal activation measures (functional magnetic resonance imaging (fMRI)) were acquired. Individuals exposed to RA showed a generalized (that is, not CS- specific) fear recall and ROF, whereas unexposed individuals showed differential (that is, CS+ specific) fear recall and ROF on an autonomic level despite no group differences during fear acquisition and extinction learning. These group differences in ROF were accompanied by corresponding activation differences in brain areas known to be involved in fear processing and differentiability/generalization of ROF (that is, hippocampus). In addition, dimensional measures of RA, CA and lifetime adversity were negatively correlated with differential skin conductance responses (SCRs) during ROF and hippocampal activation. As discriminating signals of danger and safety, as well as a tendency for overgeneralization, are core features in clinically anxious populations, these deficits may specifically contribute to relapse risk following exposure to adversity, in particular to recent adversity. Hence, our results may provide first and novel insights into the possible mechanisms mediating enhanced relapse risk following exposure to (recent) adversity, which may guide the development of effective pre- and intervention programs.

Relapse represents a major limitation to long-term remission of psychopathology (anxiety, addiction). Relapse of anxiety can be modeled in the laboratory as return of fear (ROF) following un-signaled re-presentation of the aversive event (reinstatement, RI) after extinction. In humans, response enhancement to both the CS+ and CS- (generalized RI) or specifically to the CS+ (differential RI) has been described following RI. The (psychological) mechanisms and boundary conditions underlying these different RI qualities were investigated in 76 healthy participants using autonomic measures and functional magnetic resonance imaging. Our results suggest that both processes reflect distinct albeit intertwined (psychological) processes which are reflected in different neural activation patterns. Differential RI was linked to CS+ related hippocampal activation and CS- related disinhibition of the ventromedial prefrontal cortex (vmPFC). The latter likely contributes to robust generalized RI which was mirrored in thalamic and visual areas (as well as the bed nucleus of the striatum and inusula) possibly indicating generally facilitated salience processing. In addition, we also present data on experimental boundary conditions of RI (trial sequence effects, time stability). Taken together, this first comprehensive analysis of RI-induced ROF aids not only experimental research on ROF but also understanding of factors promoting clinical relapse and the role of the vmPFC.

Cortical oscillations demonstrate a relationship with cognition. Moreover, they also exhibit associations with task performance and psychiatric mental disorders. This being the case, the modification of oscillations has become one of the key interests of neuroscientific approaches for cognitive enhancement. For such kind of alterations, neurofeedback (NF) of brain activity constitutes a promising tool. Concerning specific higher cognitive functions, frontal-midline theta (fm-theta) has been suggested as an important indicator of relevant brain processes. This paper presents a novel approach for an individualized, eight-session NF training to enhance fm-theta. An individual's dominant fm-theta frequency was determined based on experiments tapping executive functions. Effects of the actual NF training were compared to a pseudo-NF training. Participants of the pseudo-NF training experienced a comparable degree of motivation and commitment as the subjects of the actual NF training, but found the "training" slightly easier. In comparison to the pseudo-NF training, proper NF training significantly enhanced fm-theta amplitude in the actual training sessions, as well as during the whole course of training. However, unspecific changes in the alpha and beta frequency ranges found with both the actual NF and the pseudo-NF training groups emphasize the relevance of active control groups for neurofeedback studies.

Humans differ in their ability to learn how to control their own brain activity by neurofeedback. However, neural mechanisms underlying these inter-individual differences, which may determine training success and associated cognitive enhancement, are not well-understood. Here, it is asked whether neurofeedback success of frontal-midline (fm) theta, an oscillation related to higher cognitive functions, could be predicted by the morphology of brain structures known to be critically involved in fm-theta generation. Nineteen young, right-handed participants underwent magnetic resonance imaging of T1-weighted brain images, and took part in an individualized, eight-session neurofeedback training in order to learn how to enhance activity in their fm-theta frequency band. Initial training success, measured at the second training session, was correlated with the final outcome measure. We found that the inferior, superior, and middle frontal cortices were not associated with training success. However, volume of the midcingulate cortex as well as volume and concentration of the underlying white matter structures act as predictor variables for the general responsiveness to training. These findings suggest a neuroanatomical foundation for the ability to learn to control one's own brain activity.