Multimodal Assessment of Long-Term Memory Recall and Reinstatement in a Combined Cue and Context Fear Conditioning and Extinction Paradigm in Humans

Learning to predict danger via associative learning processes is critical for adaptive behaviour. After successful extinction, persisting fear memories often emerge as returning fear. Investigation of return of fear phenomena, e.g. reinstatement, have only recently began and to date, many critical questions with respect to reinstatement in human populations remain unresolved. Few studies have separated experimental phases in time even though increasing evidence shows that allowing for passage of time (and consolidation) between experimental phases has a major impact on the results. In addition, studies have relied on a single psychophysiological dimension only (SCRs/SCL or FPS) which hamper…

Excitability regulation in the dorsomedial prefrontal cortex during sustained instructed fear responses: a TMS-EEG study

AbstractThreat detection is essential for protecting individuals from adverse situations, in which a network of amygdala, limbic regions and dorsomedial prefrontal cortex (dmPFC) regions are involved in fear processing. Excitability regulation in the dmPFC might be crucial for fear processing, while abnormal patterns could lead to mental illness. Notwithstanding, non-invasive paradigms to measure excitability regulation during fear processing in humans are missing. To address this challenge we adapted an approach for excitability characterization, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS) over the dmPFC during an instructed fear paradigm, to dynamica…

A Dopaminergic Basis for Fear Extinction.

It is a joyous relief when an event we dread fails to materialize. In fear extinction, the appetitive nature of an omitted aversive event is not a mere epiphenomenon but drives the reduction of fear responses and the formation of long-term extinction memories. Dopamine emerges as key neurobiological mediator of these related processes.

Corrigendum to "Intervention studies to foster resilience - A systematic review and proposal for a resilience framework in future intervention studies" [Clinical Psychology Review 59 (2018) 78-100].

The frequent stressor and mental health monitoring-paradigm: a proposal for the operationalization and measurement of resilience and the identification of resilience processes in longitudinal observational studies

Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time …

Pattern analyses reveal separate experience-based fear memories in the human right Amygdala

Learning fear via the experience of contingencies between a conditioned stimulus (CS) and an aversive unconditioned stimulus (US) is often assumed to be fundamentally different from learning fear via instructions. An open question is whether fear-related brain areas respond differently to experienced CS–US contingencies than to merely instructed CS–US contingencies. Here, we contrasted two experimental conditions where subjects were instructed to expect the same CS–US contingencies while only one condition was characterized by prior experience with the CS–US contingency. Using multivoxel pattern analysis of fMRI data, we found CS-related neural activation patterns in the right amygdala (but…

Dopamine Related Genes Differentially Affect Declarative Long-Term Memory in Healthy Humans

In humans, monetary reward can promote behavioral performance including response times, accuracy, and subsequent recognition memory. Recent studies have shown that the dopaminergic system plays an essential role here, but the link to interindividual differences remains unclear. To further investigate this issue, we focused on previously described polymorphisms of genes affecting dopaminergic neurotransmission: DAT1 40 base pair (bp), DAT1 30 bp, DRD4 48 bp, and cannabinoid receptor type 1 (CNR1). Specifically, 669 healthy humans participated in a delayed recognition memory paradigm on two consecutive days. On the first day, male vs. female faces served as cues predicting an immediate moneta…

Excitability regulation in the dorsomedial prefrontal cortex during sustained instructed fear responses: a TMS-EEG study

AbstractBackgroundThreat detection is essential for protecting individuals from precarious situations. Early studies suggested a network of amygdala, limbic regions and dorsomedial prefrontal cortex (dmPFC) involved in fear processing. Excitability regulation in the dmPFC might be crucial for physiological fear processing, while an abnormal excitability pattern could lead to mental illness. Non-invasive paradigms to measure excitability regulation during fear processing in humans are missing.MethodsWe adapted an experimental approach of excitability characterization using electroencephalography (EEG) recordings and transcranial magnetic stimulation (TMS) over the dmPFC during an instructed …

Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition o…

Replication of fMRI group activations in the neuroimaging battery for the Mainz Resilience Project (MARP)

Abstract Motivated by the recent replicability crisis we tested replicability of functional magnetic resonance imaging (fMRI) group activations in two independent samples. An identical behavioral and fMRI test battery for the longitudinal investigation of stress resilience mechanisms was developed for the Mainz Resilience Project (MARP) and conducted in a discovery (N = 54) and a replication sample (N = 103). The test battery consisted of a stress reactivity task, a reward sensitivity task, a fear conditioning and extinction paradigm, two volitional reappraisal tasks and an emotional interference inhibition task. Replicability of group activations was tested with the Jaccard index and the I…

Standalone Smartphone Cognitive Behavioral Therapy–Based Ecological Momentary Interventions to Increase Mental Health: Narrative Review

Background A growing number of psychological interventions are delivered via smartphones with the aim of increasing the efficacy and effectiveness of these treatments and providing scalable access to interventions for improving mental health. Most of the scientifically tested apps are based on cognitive behavioral therapy (CBT) principles, which are considered the gold standard for the treatment of most mental health problems. Objective This review investigates standalone smartphone-based ecological momentary interventions (EMIs) built on principles derived from CBT that aim to improve mental health. Methods We searched the MEDLINE, PsycINFO, EMBASE, and PubMed databases for peer-reviewed …

Increases of negative affect following daily hassles are not moderated by neuroticism: An ecological momentary assessment study

The occurrence of daily hassles is associated with increased subsequent levels of negative affect. Neuroticism has been found to exacerbate this effect. So far, most research used single-item measures for the assessment of daily hassles or relied on daily diary studies. This study aimed to examine the interrelations of daily hassles, negative affect reactivity, and neuroticism in daily life employing an extensive inventory of daily hassles. Seventy participants (18-30 years; M = 23.9 years, 59% female) completed a 4-week smartphone-based ecological momentary assessment study reporting the occurrence and perceived strain of daily hassles as well as negative affect at five semi-random signals…

Making a mountain out of a molehill: on the role of the rostral dorsal anterior cingulate and dorsomedial prefrontal cortex in conscious threat appraisal, catastrophizing, and worrying.

According to appraisal theories fear and anxiety are elicited by the subjective evaluation of a situation or internal state as threatening. From this perspective anxiety disorders result from maladaptive, exaggerated threat appraisals that over-estimate the threatening consequences of often innocuous stimuli and situations. When these threat over-estimations occur at the level of conscious processing, they are referred to as catastrophizing and worrying. Both are major pathogenic processes in many clinical theories of anxiety. Until recently, little has been known about the neurobiological basis of normal and pathological conscious threat appraisal. Here, we review functional neuroimaging s…

MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits

Regulator of G-protein Signaling 2 (RGS2) is a key regulator of G-protein-coupled signaling pathways involved in fear and anxiety. Data from rodent models and genetic analysis of anxiety-related traits and disorders in humans suggest down-regulation of RGS2 expression to be a risk factor for anxiety. Here we investigated, whether genetic variation in microRNAs mediating posttranscriptional down-regulation of RGS2 may be a risk factor for anxiety as well. 75 microRNAs predicted to regulate RGS2 were identified by four bioinformatic algorithms and validated experimentally by luciferase reporter gene assays. Specificity was confirmed for six microRNAs (hsa-miR-1271-5p, hsa-miR-22-3p, hsa-miR-3…

Individualizing deep dynamic models for psychological resilience data

ABSTRACTDeep learning approaches can uncover complex patterns in data. In particular, variational autoencoders (VAEs) achieve this by a non-linear mapping of data into a low-dimensional latent space. Motivated by an application to psychological resilience in the Mainz Resilience Project (MARP), which features intermittent longitudinal measurements of stressors and mental health, we propose an approach for individualized, dynamic modeling in this latent space. Specifically, we utilize ordinary differential equations (ODEs) and develop a novel technique for obtaining person-specific ODE parameters even in settings with a rather small number of individuals and observations, incomplete data, an…

A ventral striatal prediction error signal in human fear extinction learning.

Animal studies have shown that the prediction error (PE) signal that drives fear extinction learning is encoded by phasic activity of midbrain dopamine (DA) neurons. Thus, the extinction PE resembles the appetitive PE that drives reward learning. In humans, fear extinction learning is less well understood. Using computational neuroimaging, a previous study from our group reported hemodynamic activity in the left ventral putamen, a subregion of the ventral striatum (VS), to correlate with a PE function derived from a formal associative learning model. The activity was modulated by genetic variation in a DA-related gene. To conceptually replicate and extend this finding, we here asked whether…

Deconstructing and reconstructing resilience: a dynamic network approach

Resilience is still often viewed as a unitary personality construct that, as a kind of anti-nosological entity, protects individuals against stress-related mental problems. However, increasing evidence indicates that the maintenance of mental health in the face of adversity results from complex and dynamic processes of adaptation to stressors that involve the activation of several separable protective factors. Such resilience factors can reside at biological, psychological and social levels and may include stable predispositions (such as genotype or personality traits) and malleable properties, skills, capacities or external circumstances (such as gene expression patterns, emotion regulatio…

Increased Neural Activity in Mesostriatal Regions after Prefrontal Transcranial Direct Current Stimulation and L-DOPA Administration

Dopamine dysfunction is associated with a wide range of neuropsychiatric disorders commonly treated pharmacologically or invasively. Recent studies provide evidence for a nonpharmacological and noninvasive alternative that allows similar manipulation of the dopaminergic system: transcranial direct current stimulation (tDCS). In rodents, tDCS has been shown to increase neural activity in subcortical parts of the dopaminergic system, and recent studies in humans provide evidence that tDCS over prefrontal regions induces striatal dopamine release and affects reward-related behavior. Based on these findings, we used fMRI in healthy human participants and measured the fractional amplitude of low…

Reconceptualising resilience within a translational framework is supported by unique and brain-region specific transcriptional signatures in mice

ABSTRACTChronic social defeat (CSD) in mice has been increasingly employed in experimental resilience research. Particularly, the degree of CSD-induced social avoidance is used to classify animals into resilient (socially non-avoidant) versus susceptible (avoidant). In-spired by human data pointing to threat-safety discrimination and responsiveness to extinction training of aversive memories as characteristics of resilient individuals, we here describe a translationally informed stratification which identified three phenotypic subgroups of mice following CSD: the Discriminating-avoiders, characterised by successful social threat-safety discrimination and successful extinction of social avoi…

The Functional Role of Large-scale Brain Network Coordination in Placebo-induced Anxiolysis

Abstract Anxiety reduction through mere expectation of anxiolytic treatment effects (placebo anxiolysis) has enormous clinical importance. Recent behavioral and electrophysiological data suggest that placebo anxiolysis involves reduced vigilance and enhanced internalization of attention; however, the underlying neurobiological mechanisms are not yet clear. Given the fundamental function of intrinsic connectivity networks (ICNs) in basic cognitive processes, we investigated ICN activity patterns associated with externally and internally directed mental states under the influence of an anxiolytic placebo medication. Based on recent findings, we specifically analyzed the functional role of the…

Effects of post-extinction l-DOPA administration on the spontaneous recovery and reinstatement of fear in a human fMRI study

Relapse is a pertinent problem in the treatment of anxiety disorders. In the laboratory, relapse is modeled as return of conditioned fear responses after successful fear extinction and is explained by insufficient retrieval and/or expression of the fear-inhibitory extinction memory that is generated during extinction learning. We have shown in mice and humans that return of fear can be prevented by administration of a single dose of the dopamine precursor l-3,4-dihydroxyphenylalanine (l-DOPA) immediately after extinction. In mice, this effect could be attributed to an enhancement of extinction memory consolidation. In our human study, we could not exclude that l-DOPA might have acted by int…

A conceptual framework for the neurobiological study of resilience.

AbstractThe well-replicated observation that many people maintain mental health despite exposure to severe psychological or physical adversity has ignited interest in the mechanisms that protect against stress-related mental illness. Focusing on resilience rather than pathophysiology in many ways represents a paradigm shift in clinical-psychological and psychiatric research that has great potential for the development of new prevention and treatment strategies. More recently, research into resilience also arrived in the neurobiological community, posing nontrivial questions about ecological validity and translatability. Drawing on concepts and findings from transdiagnostic psychiatry, emoti…

Fear expression and return of fear following threat instruction with or without direct contingency experience

Prior research showed that mere instructions about the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US) can generate fear reactions to the CS. Little is known, however, about the extent to which actual CS-US contingency experience adds anything beyond the effect of contingency instructions. Our results extend previous studies on this topic in that it included fear potentiated startle as an additional dependent variable and examined return of fear (ROF) following reinstatement. We observed that CS-US pairings can enhance fear reactions beyond the effect of contingency instructions. Moreover, for all measures of fear, instructions elicited immediate fear reac…

Where There is Smoke There is Fear-Impaired Contextual Inhibition of Conditioned Fear in Smokers

The odds-ratio of smoking is elevated in populations with neuropsychiatric diseases, in particular in the highly prevalent diagnoses of post-traumatic stress and anxiety disorders. Yet, the association between smoking and a key dimensional phenotype of these disorders—maladaptive deficits in fear learning and fear inhibition—is unclear. We therefore investigated acquisition and memory of fear and fear inhibition in healthy smoking and non-smoking participants (N=349, 22% smokers). We employed a well validated paradigm of context-dependent fear and safety learning (day 1) including a memory retrieval on day 2. During fear learning, a geometrical shape was associated with an aversive electric…

Population-based validation of a German version of the Brief Resilience Scale.

Smith and colleagues developed the Brief Resilience Scale (BRS) to assess the individual ability to recover from stress despite significant adversity. This study aimed to validate the German version of the BRS. We used data from a population-based (sample 1: n = 1.481) and a representative (sample 2: n = 1.128) sample of participants from the German general population (age ≥ 18) to assess reliability and validity. Confirmatory factor analyses (CFA) were conducted to compare one- and two-factorial models from previous studies with a method-factor model which especially accounts for the wording of the items. Reliability was analyzed. Convergent validity was measured by correlating BRS scores …

Advancing empirical resilience research.

AbstractWe are delighted by the broad, intense, and fruitful discussion in reaction to our target article. A major point we take from the many comments is a prevailing feeling in the research community that we need significantly and urgently to advance resilience research, both by sharpening concepts and theories and by conducting empirical studies at a much larger scale and with a much more extended and sophisticated methodological arsenal than is the case currently. This advancement can be achieved only in a concerted international collaborative effort. In our response, we try to argue that an explicitly atheoretical, purely observational definition of resilience and a transdiagnostic, qu…

Amygdala response to anticipation of dyspnea is modulated by 5-HTTLPRgenotype

Dyspnea anticipation and perception varies largely between individuals. To investigate whether genetic factors related to negative affect such as the 5-HTTLPR polymorphism impact this variability, we investigated healthy, 5-HTTLPR stratified volunteers using resistive load induced dyspnea together with fMRI. Alternating blocks of severe and mild dyspnea ("perception") were differentially cued ("anticipation") and followed by intensity and unpleasantness ratings. In addition, volunteers indicated their anticipatory fear during the anticipation periods. There were no genotype-based group differences concerning dyspnea intensity and unpleasantness or brain activation during perception of sever…

Construct Validity and Population-Based Norms of the German Brief Resilience Scale (BRS).

Abstract. The Brief Resilience Scale (BRS) measures the ability to recover from stress. To provide further evidence for construct validity of the German BRS and to determine population-based norms, a large sample (N = 1,128) representative of the German adult population completed a survey including the BRS and instruments measuring perceived stress and the resilience factors optimism, self-efficacy, and locus of control. Confirmatory factor analyses showed best model fit for a five-factor model differentiating the ability to recover from stress from the three resilience factors. On the basis of latent and manifest correlations, convergent and discriminant validity of the BRS were fair to g…

Neural Mechanisms of Placebo Anxiolysis

The beneficial effects of placebo treatments on fear and anxiety (placebo anxiolysis) are well known from clinical practice, and there is strong evidence indicating a contribution of treatment expectations to the efficacy of anxiolytic drugs. Although clinically highly relevant, the neural mechanisms underlying placebo anxiolysis are poorly understood. In two studies in humans, we tested whether the administration of an inactive treatment along with verbal suggestions of anxiolysis can attenuate experimentally induced states of phasic fear and/or sustained anxiety. Phasic fear is the response to a well defined threat and includes attentional focusing on the source of threat and concomitant …

Single dose of l-dopa makes extinction memories context-independent and prevents the return of fear

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression--and, thus, return of fear--is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly…

DFG-Sonderforschungsbereich SFB1193 „Neurobiologie der Resilienz gegenüber stressinduzierter psychischer Dysfunktion: Mechanismen verstehen und Prävention fördern“

Zusammenfassung Stressbedingte psychische Erkrankungen wie Angst, Depression, chronischer Schmerz oder Sucht können großes individuelles Leid sowie hohe gesellschaftliche und wirtschaftliche Folgekosten nach sich ziehen. Fortschritte in unserem Verständnis der zugrunde liegenden Krankheitsmechanismen und insbesondere in der Entwicklung neuer Therapien waren trotz großer Forschungsanstrengungen in den letzten Jahrzehnten nur begrenzt; stressbedingte Erkrankungen sind immer noch weit verbreitet. Wir glauben daher, dass es an der Zeit ist, pathophysiologische Forschung durch einen alternativen Ansatz zu ergänzen, der darin besteht, Schutzmechanismen zu untersuchen, die die Aufrechterhaltung de…

Mismatch or allostatic load? Timing of life adversity differentially shapes gray matter volume and anxious temperament

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, res…

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases

BACKGROUND: Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. METHODS: We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs) fear and unconditioned stimulus expectancy ratings were obtained. RESULTS: We included 377 individuals (261 women) in our study. Robust sex differences were observe…

A Combined Behavioral and Neuroimaging Battery to Test Positive Appraisal Style Theory of Resilience in Longitudinal Studies

AbstractResilience is the maintenance or rapid recovery of mental health during and after stressor exposure. It is becoming increasingly clear that resilience results from a complex and dynamic process of adaptation to stressors involving the biological, psychological and social levels. Positive appraisal style theory of resilience (PASTOR) claims that the common final pathway to maintained mental health lies in the non-negative (non-catastrophizing, non-pessimistic) appraisal of potential stressors, permitting the organism to fine-tune stress responses to optimal levels, thus avoiding unnecessary stress, inefficient deployment of resources and concomitant deleterious allostatic load effect…

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

Contains fulltext : 177350.pdf (Publisher’s version ) (Closed access) 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 x 10-8; rs191260602, P=3.9 x 10-8). We followed up on this finding in a larger dimensional AC…

Assessment of Microstressors in Adults: Questionnaire Development and Ecological Validation of the Mainz Inventory of Microstressors

Background Many existing scales for microstressor assessment do not differentiate between objective (ie, observable) stressor events and stressful cognitions or concerns. They often mix items assessing objective stressor events with items measuring other aspects of stress, such as perceived stressor severity, the evoked stress reaction, or further consequences on health, which may result in spurious associations in studies that include other questionnaires that measure such constructs. Most scales were developed several decades ago; therefore, modern life stressors may not be represented. Ecological momentary assessment (EMA) allows for sampling of current behaviors and experiences in real…

Author response: Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Intervention studies to foster resilience – A systematic review and proposal for a resilience framework in future intervention studies

Psychological resilience refers to the phenomenon that many people are able to adapt to the challenges of life and maintain mental health despite exposure to adversity. This has stimulated research on training programs to foster psychological resilience. We evaluated concepts, methods and designs of 43 randomized controlled trials published between 1979 and 2014 which assessed the efficacy of such training programs and propose standards for future intervention research based on recent developments in the field. We found that concepts, methods and designs in current resilience intervention studies are of limited use to properly assess efficacy of interventions to foster resilience. Major pro…

Transient and sustained BOLD signal time courses affect the detection of emotion-related brain activation in fMRI.

A tremendous amount of effort has been dedicated to unravel the functional neuroanatomy of the processing and regulation of emotion, resulting in a well-described picture of limbic, para-limbic and prefrontal regions involved. Studies applying functional magnetic resonance imaging (fMRI) often use the block-wise presentation of stimuli with affective content, and conventionally model brain activation as a function of stimulus or task duration. However, there is increasing evidence that regional brain responses may not always translate to task duration and rather show stimulus onset-related transient time courses. We assume that brain regions showing transient responses cannot be detected in…