Distributed neural representations of conditioned threat in the human brain.

Detecting and responding to threat engages several neural nodes including the amygdala, hippocampus, insular cortex, and medial prefrontal cortices. Recent propositions call for the integration of more distributed neural nodes that process sensory and cognitive facets related to threat. Integrative, sensitive, and reproducible distributed neural decoders for the detection and response to threat and safety have yet to be established. We combine functional MRI data across varying threat conditioning and negative affect paradigms from 1465 participants with multivariate pattern analysis to investigate distributed neural representations of threat and safety. The trained decoders sensitively and specifically distinguish between threat and safety cues across multiple datasets. We further show that many neural nodes dynamically shift representations between threat and safety. Our results establish reproducible decoders that integrate neural circuits, merging the well-characterized 'threat circuit' with sensory and cognitive nodes, discriminating threat from safety regardless of experimental designs or data acquisition parameters.

Dorsal anterior cingulate cortex activity during cognitive challenge in social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is associated with aberrant emotional information processing while little is known about non-emotional cognitive processing biases. The dorsal anterior cingulate cortex (dACC) has been implicated in SAD neuropathology and is activated both by emotional and non-affective cognitive challenges like the Multisource Interference Task (MSIT). METHODS: Here, we used fMRI to compare dACC activity and test performance during MSIT in 69 SAD patients and 38 healthy controls. In addition to patient-control comparisons, we examined whether neural activity in the dACC correlated with social anxiety, trait anxiety or depression levels. RESULTS: The MSIT activated the dACC as expected but with no differences in task performance or neural reactivity between SAD patients and controls. There were no significant correlations between dACC activity and social or trait anxiety symptom severity. In patients, there was a significant negative correlation between dACC activity and depressive symptoms. CONCLUSIONS: In absence of affective challenge, we found no disorder-related cognitive profile in SAD patients since neither MSIT task performance nor dACC neural activity deviated in patients relative to controls.

Whole brain correlates of individual differences in skin conductance responses during discriminative fear conditioning to social cues.

Understanding the neural basis for individual differences in the skin conductance response (SCR) during discriminative fear conditioning may inform on our understanding of autonomic regulation in fear-related psychopathology. Previous region-of-interest (ROI) analyses have implicated the amygdala in regulating conditioned SCR, but whole brain analyses are lacking. This study examined correlations between individual differences in SCR during discriminative fear conditioning to social stimuli and neural activity throughout the brain, by using data from a large functional magnetic resonance imaging study of twins (N = 285 individuals). Results show that conditioned SCR correlates with activity in the dorsal anterior cingulate cortex/anterior midcingulate cortex, anterior insula, bilateral temporoparietal junction, right frontal operculum, bilateral dorsal premotor cortex, right superior parietal lobe, and midbrain. A ROI analysis additionally showed a positive correlation between amygdala activity and conditioned SCR in line with previous reports. We suggest that the observed whole brain correlates of SCR belong to a large-scale midcingulo-insular network related to salience detection and autonomic-interoceptive processing. Altered activity within this network may underlie individual differences in conditioned SCR and autonomic aspects of psychopathology.

A neuroimaging study of interpersonal distance in identical and fraternal twins.

Keeping appropriate interpersonal distance is an evolutionary conserved behavior that can be adapted based on learning. Detailed knowledge on how interpersonal space is represented in the brain and whether such representation is genetically influenced is lacking. We measured brain function using functional magnetic resonance imaging in 294 twins (71 monozygotic, 76 dizygotic pairs) performing a distance task where neural responses to human figures were compared to cylindrical blocks. Proximal viewing distance of human figures was compared to cylinders facilitated responses in the occipital face area (OFA) and the superficial part of the amygdala, which is consistent with these areas playing a role in monitoring interpersonal distance. Using the classic twin method, we observed a genetic influence on interpersonal distance related activation in the OFA, but not in the amygdala. Results suggest that genetic factors may influence interpersonal distance monitoring via the OFA whereas the amygdala may play a role in experience-dependent adjustments of interpersonal distance.

Genetic Influence on Nociceptive Processing in the Human Brain-A Twin Study.

Nociceptive processing in the human brain is complex and involves several brain structures and varies across individuals. Determining the structures that contribute to interindividual differences in nociceptive processing is likely to improve our understanding of why some individuals feel more pain than others. Here, we found specific parts of the cerebral response to nociception that are under genetic influence by employing a classic twin-design. We found genetic influences on nociceptive processing in the midcingulate cortex and bilateral posterior insula. In addition to brain activations, we found genetic contributions to large-scale functional connectivity (FC) during nociceptive processing. We conclude that additive genetics influence specific brain regions involved in nociceptive processing. The genetic influence on FC during nociceptive processing is not limited to core nociceptive brain regions, such as the dorsal posterior insula and somatosensory areas, but also involves cognitive and affective brain circuitry. These findings improve our understanding of human pain perception and increases chances to find new treatments for clinical pain.

Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial.

It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

Higher- and lower-order personality traits and cluster subtypes in social anxiety disorder.

Social anxiety disorder (SAD) can come in different forms, presenting problems for diagnostic classification. Here, we examined personality traits in a large sample of patients (N = 265) diagnosed with SAD in comparison to healthy controls (N = 164) by use of the Revised NEO Personality Inventory (NEO-PI-R) and Karolinska Scales of Personality (KSP). In addition, we identified subtypes of SAD based on cluster analysis of the NEO-PI-R Big Five personality dimensions. Significant group differences in personality traits between patients and controls were noted on all Big Five dimensions except agreeableness. Group differences were further noted on most lower-order facets of NEO-PI-R, and nearly all KSP variables. A logistic regression analysis showed, however, that only neuroticism and extraversion remained significant independent predictors of patient/control group when controlling for the effects of the other Big Five dimensions. Also, only neuroticism and extraversion yielded large effect sizes when SAD patients were compared to Swedish normative data for the NEO-PI-R. A two-step cluster analysis resulted in three separate clusters labelled Prototypical (33%), Introvert-Conscientious (29%), and Instable-Open (38%) SAD. Individuals in the Prototypical cluster deviated most on the Big Five dimensions and they were at the most severe end in profile analyses of social anxiety, self-rated fear during public speaking, trait anxiety, and anxiety-related KSP variables. While additional studies are needed to determine if personality subtypes in SAD differ in etiological and treatment-related factors, the present results demonstrate considerable personality heterogeneity in socially anxious individuals, further underscoring that SAD is a multidimensional disorder.

The effect of mindfulness training on extinction retention.

Anxiety and trauma related disorders are highly prevalent, causing suffering and high costs for society. Current treatment strategies, although effective, only show moderate effect-sizes when compared to adequate control groups demonstrating a need to develop new forms of treatment or optimize existing ones. In order to achieve this, an increased understanding of what mechanisms are involved is needed. An emerging literature indicates that mindfulness training (MFT) can be used to treat fear and anxiety related disorders, but the treatment mechanisms are unclear. One hypothesis, largely based on findings from neuroimaging studies, states that MFT may improve extinction retention, but this has not been demonstrated empirically. To investigate this question healthy subjects either completed a 4-week MFT- intervention delivered through a smart-phone app (n = 14) or were assigned to a waitlist (n = 15). Subsequently, subjects participated in a two-day experimental protocol using pavlovian aversive conditioning, evaluating acquisition and extinction of threat-related responses on day 1, and extinction retention on day 2. Results showed that the MFT group displayed reduced spontaneous recovery of threat related arousal responses, as compared to the waitlist control group, on day 2. MFT did not however, have an effect on either the acquisition or extinction of conditioned responses day 1. This clarifies the positive effect of MFT on emotional functioning and could have implications for the treatment of anxiety and trauma related disorders.

The effect of immersive virtual reality on proximal and conditioned threat.

Virtual reality lets the user be immersed in a 3-dimensional environment, which can enhance certain emotional responses to stimuli relative to experiencing them on a flat computer screen. We here tested whether displaying two different types of threats in immersive virtual reality enhanced threat related autonomic responses measured by skin conductance responses (SCRs). We studied innate and learned threat responses because these types of threats have been shown to depend on different neural circuits in animals. Therefore, it is possible that immersive virtual reality may modulate one of these threats but not the other. Innate threat responses were provoked by the sudden appearance of characters at proximal egocentric distance, which were compared to the sudden appearance of distant characters (proximal threat). Learned threat responses were studied by conditioning two of the characters to an electric shock (conditioned threat) and contrasting SCRs to these characters with SCRs to two other characters that were never paired with shock. We found that displaying stimuli in immersive virtual reality enhanced proximal threat responses but not conditioned threat responses. Findings show that immersive virtual reality can enhance an innate type of threat responses without affecting a learned threat response, suggesting that separate neural pathways serve these threat responses.

Teaching psychiatry to large groups in society.

BACKGROUND: There is a need to educate a range of professionals in caring for individuals with long-term mental disability who reside within our communities. Empathy alone is insufficient. The Kognus 4-Step Education Program was developed to achieve this goal. METHOD: The program consisted of independent courses, including an 18-session basic course on psychiatric disability (on-site or online), advanced courses, and highly specialized training programs (Nidotherapy/Peer Consultation). Experts lectured together with clients with psychiatric disabilities. We first report Swedish reforms in which institutionalized patients were relocated to semi-independent individual households. We then describe the design and implementation of the education program. Approximately 50% of participants who were younger than 36 years old lacked any healthcare education. The participants' backgrounds, perceptions, participation in the education program, and costs are presented. RESULTS: Between 2009 and 2014, 8959 participants attended the Kognus psychiatry courses online or on-site in Stockholm (basic on-site course, n = 2111; online course, n = 4480; advanced courses, n = 2322; highly specialized programs, n = 46). A total of 73% of the participants satisfactorily attended the basic sessions on-site compared with 11% of the online participants. The developers conducted the education program for the first 3 years. Thereafter, another course provider continued the program with other types of participants. The program was perceived to be equally interesting and meaningful to participants with low and high levels of education, demonstrating the generalizability of the program. The quality of the basic and advanced courses was rated as 4.4 and 4.3, respectively, on a 5-point Likert scale. CONCLUSIONS: Personnel without appropriate education who work with people with psychiatric/intellectual disabilities can be educated in large numbers. The Kognus program represents a novel and successful way of training people who have no formal education about some essentials of good mental healthcare. Moreover, the model can be easily implemented elsewhere.

Biological preparedness and resistance to extinction of skin conductance responses conditioned to fear relevant animal pictures: A systematic review.

Preparedness theory is one of the most influential ideas in explaining the origin of specific phobias. The theory proposes that fear conditioning is selective to animals that have posed a threat to survival throughout human evolution, and that acquired fear memories to such threats are resistant to extinction. We reviewed fear conditioning studies testing whether autonomic responses conditioned to pictures of snakes and spiders show greater resistance to extinction than neutral cues. We identified 32 fear conditioning experiments published in 23 studies including 1887 participants. Increased resistance to extinction of conditioned responses to snake and spider pictures was found in 10 (31%) of the experiments, whereas 22 (69%) experiments did not support the hypothesis. Thus, the body of evidence suggests that preparedness theory does not explain the origin of specific phobias.

The Immersive Virtual Reality Lab: Possibilities for Remote Experimental Manipulations of Autonomic Activity on a Large Scale.

There is a need for large-scale remote data collection in a controlled environment, and the in-home availability of virtual reality (VR) and the commercial availability of eye tracking for VR present unique and exciting opportunities for researchers. We propose and provide a proof-of-concept assessment of a robust system for large-scale in-home testing using consumer products that combines psychophysiological measures and VR, here referred to as a Virtual Lab. For the first time, this method is validated by correlating autonomic responses, skin conductance response (SCR), and pupillary dilation, in response to a spider, a beetle, and a ball using commercially available VR. Participants demonstrated greater SCR and pupillary responses to the spider, and the effect was dependent on the proximity of the stimuli to the participant, with a stronger response when the spider was close to the virtual self. We replicated these effects across two experiments and in separate physical room contexts to mimic variability in home environment. Together, these findings demonstrate the utility of pupil dilation as a marker of autonomic arousal and the feasibility to assess this in commercially available VR hardware and support a robust Virtual Lab tool for massive remote testing.

Social, proximal and conditioned threat.

Responding to threats in the environment is crucial for survival. Certain types of threat produce defensive responses without necessitating previous experience and are considered innate, whereas other threats are learned by experiencing aversive consequences. Two important innate threats are whether an encountered stimulus is a member of the same species (social threat) and whether a stimulus suddenly appears proximal to the body (proximal threat). These threats are manifested early in human development and robustly elicit defensive responses. Learned threat, on the other hand, enables adaptation to threats in the environment throughout the life span. A well-studied form of learned threat is fear conditioning, during which a neutral stimulus acquires the ability to eliciting defensive responses through pairings with an aversive stimulus. If innate threats can facilitate fear conditioning, and whether different types of innate threats can enhance each other, is largely unknown. We developed an immersive virtual reality paradigm to test how innate social and proximal threats are related to each other and how they influence conditioned fear. Skin conductance responses were used to index the autonomic component of the defensive response. We found that social threat modulates proximal threat, but that neither proximal nor social threat modulates conditioned fear. Our results suggest that distinct processes regulate autonomic activity in response to proximal and social threat on the one hand, and conditioned fear on the other.