There are phenomenological similarities between social anxiety disorder (SAD) and posttraumatic stress disorder, such as a provoking aversive event, posttraumatic stress symptoms (e.g. intrusions) in response to these events and deficient (context-dependent) fear conditioning processes. This study investigated the neural correlates of context-dependent extinction recall and fear renewal in SAD, specifically in patients with intrusions in response to an etiologically relevant aversive social event.

During functional magnetic resonance imaging a two-day context-dependent fear conditioning paradigm was conducted in 54 patients with SAD and 54 healthy controls (HC). This included fear acquisition (context A) and extinction learning (context B) on one day, and extinction recall (context B) as well as fear renewal (contexts C and A) one day later. The main outcome measures were blood oxygen level-dependent responses in regions of interest and skin conductance responses.

Patients with SAD showed reduced differential conditioned amygdala activation during extinction recall in the safe extinction context and during fear renewal in the acquisition context compared to HC. Patients with clinically relevant intrusions moreover exhibited hypoactivation of the ventromedial prefrontal cortex (vmPFC) during extinction learning, extinction recall, and fear renewal in a novel context, while amygdala activation more strongly decreased during extinction learning and increased during fear renewal in the acquisition context compared with patients without intrusions.

Our study provides first evidence that intrusions in SAD are associated with similar deficits in context-dependent regulation of conditioned fear via the vmPFC as previously demonstrated in posttraumatic stress disorder.

Difficulties in the context-dependent modulation of conditioned fear are known for posttraumatic stress disorder and may explain the occurrence of intrusive memories in safe contexts. The current study therefore investigated if reduced context-dependent modulation of conditioned fear and its underlying neural circuitry constitute risk factors for the development of analog intrusions in response to an experimental trauma.

Eighty-five healthy women participated in the trauma film paradigm to investigate the development of analog intrusions as well as explicit memory for an experimental trauma after one week and three months, respectively. Before, participants underwent a context-dependent fear conditioning paradigm during functional magnetic resonance imaging with fear acquisition in context A and extinction training in context B on a first day, as well as extinction recall in context B and fear renewal in a novel context C one day later. Skin conductance responses (SCRs) and blood oxygen level dependent responses were main outcome measures.

In addition to stronger fear acquisition in context A, stronger conditioned fear responses in the safe context B, as indicated by stronger conditioned SCRs or stronger activation of fear expressing regions during extinction learning and recall, predicted the development of long-term analog intrusions.

Stronger fear responses in safe and danger contexts were risk factors for the development of long-term analog intrusions and point to decontextualized fear memories and difficulties in the context-dependent modulation of conditioned fear. Altered fear conditioning processes and reduced storage of contextual information may cause the occurrence of fear independent of context.

Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction.

In total, 1937 twins aged 22–25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase.

Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4–0.5).

Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

In a serial compound conditioning paradigm, a sequence of several conditioned stimuli (CS) is predictive to an unconditioned stimulus (US) (e.g., CSA->CSB->US). Animal research showed that, when the US is aversive, CSA elicits the strongest conditioned response, while CSB appears redundant. These effects of primacy and proximity have never been investigated in humans.

To study the effects of temporal proximity of imminent threat and safety in serial compound conditioning.

Twenty-two participants were presented with sequences [CSA->CSB->CSC->CSD]. In 55 trials all four CS were identical vowels (e.g, [oh]), and no US was presented. In the other 55 trials, the CSA was different (CSA+, e.g., [uh]), and the CSD was followed by an electrical shock (US) 2.5 times higher than the individual pain threshold.

No ERP component distinguished between CS- and CS+ for the first three stimuli in the sequence (i.e., CSA, CSB, CSC). The last CS (CSD) elicited a strong fronto-central CNV only when it was followed by US. Moreover, already after the CSA- (which signalized that no shock would be presented on that trial) the power of alpha oscillations over the somatosensory cortex significantly increased, particularly on the side contralateral to the hand that was electrically stimulated on US trials. The alpha increment lasted up to the onset of the US.

The data indicate two possible mechanisms of adjustment to predictable threat, one of which relies on safety signals (manifested in alpha increment), and the other is related to flight response (manifested in the CNV immediately preceding the shock).

The recognition of the conditioned-unconditioned stimulus (CS-US) association in classical conditioning is referred to as contingency awareness. The neural underpinnings of contingency awareness in human fear conditioning are poorly understood.

We aimed to explore the EEG correlates of contingency awareness.

Here, we recorded electroencephalography (EEG) from a sample of 20 participants in a semantic conditioning experiment. In the acquisition phase the participants were presented with sequences of words from two semantic categories paired with tactile stimulation followed by presentation of a neutral sound (US-) ((e.g., animals -> left hand vibration -> US-, clothes -> right hand vibration -> US-). In the test phase the association violated in 50% of trials which followed by a presentation of a loud noise (US+). The participants were only instructed to listen carefully. On the basis of self-reported contingency awareness, twenty participants were divided in aware (N=12) and unaware (N=8) group.

The aware group expressed a non-lateralized effect of alpha-beta (12-23 Hz) suppression along with a more negative CNV at central channels preceding presentation of the vibration (main effect of Group). Also, CNV was more negative in expectation of US+ comparing with expectation of US- in the aware group but not in the unaware group.

The results indicate that contingency awareness is accompanied by neural patterns reflecting expectation as can be seen in the suppression of somatosensory alpha-beta activity before expected presentation of the vibration as well as in CNV in expectation of an aversive event.

Studies on fear conditioning have made important contributions to the understanding of affective learning mechanisms as well as its applications (e.g., anxiety disorders, post-traumatic stress disorder). However, central mechanisms of sleep related consolidation of fear memory in humans have been almost neglected by previous studies.

In the current study we aimed to test effects of sleep and a period wakefulness on fear conditioned responses.

In our experiment in a group 18 healthy volunteers event-related brain potentials (ERP), heart rate variability (HRV) and behavioral responses were recorded during a fear conditioning procedure presented twice, before daytime sleep (2h) or control intervention (a period of wakefulness) and after. The conditioning procedure involved pairing of a neutral tone (CS+) with a highly unpleasant sound (UCS+).

Differential conditioning manifested itself in the contingent negative variance (CNV)-like slow ERP component. Both period of sleep and wakefulness resulted in an increased amplitude of the CNV to CS+. But we did not find an interaction effect of Time (Pre-Post) by Intervention (Sleep-Wake), suggesting that sleep did not affect the conditioned response differently as compared to a period of wakefulness. An apparent increase in HRV after a period of wakefulness did not affect fear conditioned responses (CNV and valence ratings).

To summarize, the data indicate that fear memories are consolidated with the course of time with no beneficial effect of sleep; relearning of fear causes stronger differential responses as measured by slow wave amplitude but not behavior; increase of HRV does not affect fear learning.

Altered fear learning processes could be mechanistically linked to the development and/or maintenance of obsessive-compulsive disorder (OCD). From a clinical perspective, the first-line psychological treatment for OCD is cognitive-behavioral therapy (CBT), which is based on the principles of fear learning. However, no previous functional magnetic resonance imaging (fMRI) studies have evaluated the predictive capacity of regional brain activations during fear learning on CBT response in patients with OCD.

We aimed at exploring whether brain activation during fear learning in patients with OCD are associated with CBT outcome.

We assessed 18 patients with OCD and 18 healthy participants during a 2-day experimental protocol where brain activation and skin conductance responses (SCR) where assessed during fear conditioning, extinction learning, and extinction recall within the fMRI scanner. Following the protocol, patients with OCD received CBT.

We found non-significant between-group differences in SCR during fear learning. Patients with OCD showed significantly diminished activation of the dorsal anterior cingulate cortex and the right insula during fear conditioning. Importantly, our analyses revealed a significant negative association between clinical improvement after CBT and activity at the right insula during fear conditioning (x = 39, y = 12, z = -11; t = 5.64; p<0.001; k = 928). This finding is displayed in Figure 1 below.

Patients with OCD may require less fear-conditioned brain responses to achieve the same level of psychophysiological fear conditioning as healthy participants. Interestingly, insula activations during fear-conditioned responses may represent a potential predictor biomarker of response to CBT for OCD.

No significant relationships.

Sustained immune activation leads to cognitive dysfunctions, depression-, and anxiety-like behaviours in humans and rodents. It is modelled by administration of lipopolysaccharides (LPS) to induce expression of pro-inflammatory cytokines that then activate indoleamine 2,3 dioxygenase (IDO1), the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Here, we ask whether chronic IDO1 inhibition by 1-methyl-tryptophan (1-MT, added at 2 g/l in the drinking water) or chronic inhibition of tryptophan 2,3 dioxygenase (TDO2), another enzyme capable of converting tryptophan to kynurenine, by 680C91 (15 mg/kg per os), can rescue LPS-induced (0.83-mg/kg intraperitoneally) anxiety and cognitive deficits. We also investigate the acute effects of 680C91 on serotonergic, dopaminergic, and kynurenine pathway metabolites.

We examined LPS-induced deficits in trace fear conditioning and anxiety in the light–dark box and elevated plus maze (EPM) in group-housed C57Bl6/N mice. Kynurenine pathway metabolites and monoamine levels were measured via high-performance liquid chromatography.

Chronic blockade of IDO1 with 1-MT did not rescue cognitive deficits or abrogate the anxiogenic behaviour caused by LPS despite a decrease in the brain kynurenine:tryptophan ratio. However, 1-MT by itself demonstrated anxiolytic properties in the EPM. Acute and chronic inhibition of TDO2 elevated brain levels of tryptophan, while chronic inhibition of TDO2 was unsuccessful in rescuing cognitive deficits and abrogating the anxiety caused by LPS.

In line with previous studies, we show that LPS administration induces anxiety and cognitive dysfunctions in mice that however were not reversed by chronic blockade of IDO1 or TDO2 at the doses used.

Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients.

The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls.

Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation.

The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI).

In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS−) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS− were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS− during testing. No UCS was presented.

Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS−.

During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS−-related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.

Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis.

In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes.

Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity.

This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.

Fear circuitry disorders purportedly include post-traumatic stress disorder (PTSD), panic disorder, agoraphobia, social phobia and specific phobia. It is proposed that these disorders represent a cluster of anxiety disorders triggered by stressful events and lead to fear conditioning. Elevated heart rate (HR) at the time of an aversive event may reflect strength of the unconditioned response, which may contribute to fear circuitry disorders.

This prospective cohort study assessed HR within 48 h of hospital admission in 602 traumatically injured patients, who were assessed during hospital admission and within 1 month of trauma exposure for lifetime psychiatric diagnosis. At 3 months after the initial assessment, 526 patients (87%) were reassessed for PTSD, major depressive disorder, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and generalized anxiety disorder.

At the 3-month assessment there were 77 (15%) new cases of fear circuitry disorder and 87 new cases of non-fear circuitry disorder (17%). After controlling for gender, age, type of injury and injury severity, patients with elevated HR (defined as ⩾96 beats per min) at the time of injury were more likely to develop PTSD [odds ratio (OR) 5.78, 95% confidence interval (CI) 2.32–14.43], panic disorder (OR 3.46, 95% CI 1.16–10.34), agoraphobia (OR 3.90, 95% CI 1.76–8.61) and social phobia (OR 3.98, 95% CI 1.42–11.14). Elevated HR also predicted new fear circuitry disorders that were not co-morbid with a non-fear circuitry disorder (OR 7.28, 95% CI 2.14–24.79).

These data provide tentative evidence of a common mechanism underpinning the onset of fear circuitry disorders.