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.

Mediators during a Multimodal intervention for stress-induced exhaustion disorder.

Our understanding of the underlying psychological processes of development, maintenance, and treatments for stress-induced exhaustion disorder (ED) remains limited. Therefore, the current study aimed to explore whether sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility mediate change in exhaustion symptoms during a Multimodal intervention for ED based on Cognitive behavioral therapy principles. Participants (N = 913) were assessed at three time points, and mediation was explored using a two-criteria analytical model with linear mixed-effects models (criterion one) and random intercepts cross-lagged panel modeling (criterion 2). Criterion one for mediation was successfully met, as the findings indicated significant associations between time in treatment, with all suggested mediators, and exhaustion symptoms (significant ab-products). However, criterion two was not satisfied as changes in the mediators did not precede changes in exhaustion symptoms. Therefore, mediation could not be established. Instead, changes in the suggested mediators appeared to result from changes in exhaustion symptoms. Consequently, sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility appear to improve in conjunction with exhaustion symptoms during treatment, where improvement in exhaustion is indicated as the main driving factor, based on this exploratory analysis. The implications of these findings are contextualized within a broader framework of process-based therapy.

Predictors and sub-groups in the treatment of stress-induced exhaustion disorder.

Little is known about psychological interventions for stress-induced Exhaustion disorder (ED), and there is a need for more research to improve the outcomes obtained in treatments. The present study examines predictors of improvement, including sub-group responses, in a large sample of ED patients receiving a Multimodal intervention (MMI) based on Cognitive Behavior Therapy (N = 915). In step one, available variables were explored separately as predictors of improvement in ED symptoms. In step two, sub-groups were explored through Latent Class Analysis to reduce the heterogeneity observed in the larger group and to investigate whether combining the variables from step one predicted symptom improvement. Younger age, no previous sick leave due to ED, and scoring high on anxiety, depression, insomnia, perfectionism, and treatment credibility emerged as separate predictors of improvement. In the sub-group analyses, a sub-group including participants who were single and had a lower income showed less improvement. Overall, people with ED participating in MMI report symptom improvement regardless of characteristics before treatment. However, the present findings do have the potential to inform future treatments for ED, as they highlight perfectionism as a predictor of improvement and the importance of assessing treatment credibility during treatment.

Psychometric evaluation of the Swedish Multidimensional Psychological Flexibility Inventory (MPFI).

Psychiatric disorders are common, and reliable measures are crucial for research and clinical practice. A cross-diagnostic construct that can be used to index treatment outcomes as well as prevalence of psychological ill health is psychological flexibility. The aim of this study was to validate a Swedish version of the Multidimensional Psychological Flexibility Inventory (MPFI). The MPFI has 12 subscales, six of which measure flexibility, and six that measure inflexibility. Using confirmatory factor analysis in a community sample of 670 participants, we found that a model with two higher order factors had satisfactory fit (CFI = .933) and a 12-factor model had the best fit to the data (CFI = .955). All 12 subscales showed adequate reliability (CRs = .803-.933) and the factor structure was similar across age groups and gender. Findings suggest that the Swedish version of the MPFI is a reliable instrument that can be used to index psychological flexibility. Potential areas for improvement of the instrument are discussed.

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.

Social Functioning in Individuals Affected by Childhood Maltreatment: Establishing a Research Agenda to Inform Interventions.

Childhood maltreatment (CM) is linked to impairments in various domains of social functioning. Here, we argue that it is critical to identify factors that underlie impaired social functioning as well as processes that mediate the beneficial health effects of positive relationships in individuals exposed to CM. Key research recommendations are presented, focusing on: (1) identifying attachment-related alterations in specific inter- and intrapersonal processes (e.g., regulation of closeness and distance) that underlie problems in broader domains of social functioning (e.g., lack of perceived social support) in individuals affected by CM; (2) identifying internal (e.g., current emotional state) and external situational factors (e.g., cultural factors, presence of close others) that modulate alterations in specific social processes; and (3) identifying mechanisms that explain the positive health effects of intact social functioning. Methodological recommendations include: (1) assessing social processes through interactive and (close to) real-life assessments inside and outside the laboratory; (2) adopting an interdisciplinary, lifespan perspective to assess social processes, using multi-method assessments; (3) establishing global research collaborations to account for cultural influences on social processes and enable replications across laboratories and countries. The proposed line of research will contribute to globally develop and refine interventions that prevent CM and further positive relationships, which - likely through buffering the effects of chronic stress and corresponding allostatic load - foster resilience and improve mental and physical health, thereby reducing personal suffering and the societal and economic costs of CM and its consequences. Interventions targeting euthymia and psychological well-being are promising therapeutic concepts in this context.

Dopamine and fear memory formation in the human amygdala.

Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

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.

GABA quantification in human anterior cingulate cortex.

γ-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter in the human brain. It has been shown that altered GABA concentration plays an important role in a variety of psychiatric and neurological disorders. The main purpose of this study was to propose a combination of PRESS and MEGA-PRESS acquisitions for absolute GABA quantification and to compare GABA estimations obtained using total choline (tCho), total creatine (tCr), and total N-acetyl aspartate (tNAA) as the internal concentration references with water referenced quantification. The second aim was to demonstrate the fitting approach of MEGA-PRESS spectra with QuasarX algorithm using a basis set of GABA, glutamate, glutamine, and NAA in vitro spectra. Thirteen volunteers were scanned with the MEGA-PRESS sequence at 3T. Interleaved water referencing was used for quantification, B0 drift correction and to update the carrier frequency of RF pulses in real time. Reference metabolite concentrations were acquired using a PRESS sequence with short TE (30 ms) and long TR (5000 ms). Absolute concentration were corrected for cerebrospinal fluid, gray and white matter water fractions and relaxation effects. Water referenced GABA estimations were significantly higher compared to the values obtained by metabolite references. We conclude that QuasarX algorithm together with the basis set of in vitro spectra improves reliability of GABA+ fitting. The proposed GABA quantification method with PRESS and MEGA-PRESS acquisitions enables the utilization of tCho, tCr, and tNAA as internal concentration references. The use of different concentration references have a good potential to improve the reliability of GABA estimation.

Standardized multimodal intervention for stress-induced exhaustion disorder: an open trial in a clinical setting.

BACKGROUND: Long-term sick-leave due to stress-related ill-health is increasing in several economically developed countries. Even though different forms of interventions are administered in regular care for stress-related disorders, such as Stress-induced Exhaustion disorder (SED), the scientific evidence for the effectiveness of such treatments is sparse. The objective of this study was to explore changes in SED-symptoms and return-to-work-rates in a large group of SED-patients participating in a standardized Multimodal intervention (MMI) in a clinical setting. METHOD: This open clinical trial tracked 390 patients who fulfilled the criteria for SED undergoing a 24-week MMI, including return-to-work-strategies. Before inclusion, all patients underwent a multi-professional assessment by a team of licensed physicians, licensed psychologists, and licensed physiotherapists. Self-rated questionnaires were administered before treatment, at treatment-start, mid-treatment, post-treatment, and at 12-month follow-up. Within-group change was evaluated over time with mixed-effects models. Beyond different symptoms, working time, sick-leave compensation, and adverse effects were also measured. RESULTS: There were significant improvements in symptoms of SED, burnout, anxiety, depression, and insomnia, with large within-group effect sizes (d = 0.91-1.76), improvements that were maintained at 12-month follow-up. Furthermore, there was a significant increase in quality of life and large improvements in average working time and sick-leave compensation. Some adverse effects were reported, mainly concerning an increase in stress, anxiety, and worry. CONCLUSION: SED-patients participating in this standardized MMI reported large symptom alleviation, increased working time and reduced sick-leave compensation, indicating a beneficial treatment. There were some adverse effects, but no more so than other psychological treatments. This study confirms previous findings that high levels of depression and anxiety decrease to sub-clinical levels during treatment, while symptoms of SED also decline, yet still persists above sub-clinical levels at 12-month follow-up. On the whole, this open clinical trial suggests that a standardized MMI, administered in a clinical setting, improves symptoms and return-to-work rates in a clinically representative SED-population. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov 2017.12.02 (Identifier: NCT03360136 ).

Decrease in amygdala activity during repeated exposure to spider images predicts avoidance behavior in spider fearful individuals.

Spider phobia is characterized by exaggerated fear of situations where spiders could be present, resulting in avoidance of such situations and compromised quality of life. An important component in psychological treatment of spider phobia is exposure to phobic situations that reduces avoidance behaviors. At the neural level, amygdala responses to phobic material are elevated, but normalizes following exposure treatment. To what extent amygdala activity decreases during a session of repeated phobic stimulation, and whether activity decrease is related to subsequent avoidance is not well studied. We hypothesized reduced amygdala activity during the course of repeated exposure to spider pictures, and that the degree of reduction would predict subsequent avoidance of spider pictures. To test our hypothesis, functional magnetic resonance imaging was performed in 45 individuals with spider fear during repeated exposure to spider pictures. Results showed that repeated exposure to spider stimuli attenuated amygdala reactivity and individual differences in activity reductions predicted subsequent avoidance behavior to spider pictures in an incentive-conflict task, with larger attenuations predicting less avoidance. At 6-month follow up, initial reductions in amygdala activation still predicted avoidance. This result demonstrates that reduction in amygdala responses is related to clinically meaningful outcomes in human anxiety, and suggests that within-session reductions in amygdala responses could be an important mechanism explaining the clinical effects of exposure therapy.

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 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.

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.

Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits.

Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

Distance to threat and risk of acute and posttraumatic stress disorder following bank robbery: A longitudinal study.

Identifying pathways through which environmental risk factors influence PTSD is important for understanding PTSD etiology. Here, we hypothesized that the physical proximity to threat influences PTSD risk by increasing ASD following trauma. One hundred six bank employees who had experienced a bank robbery participated in the study. A longitudinal design assessing ASD at day 2 and PTSD at day 30 was used to test the hypothesis. Participants also indicated their location in the bank at the time of the robbery. ASD was identified in 40 (38%) and PTSD in 16 (15%) of the robbery victims. Distance to the robber had a strong effect on ASD (OR 3.51, 95% CI 1.94-6.34) and a somewhat lesser effect on PTSD (OR 2.15, 95% CI 1.04-4.46), indicating that the effect of proximity to threat on PTSD 1 month following trauma could be mediated by its effect on ASD 2 days following trauma. Using structural equation modeling, we confirmed that the effect of distance on PTSD was fully mediated by ASD. These findings suggest that proximity to threat may increase PTSD risk by enhancing the acute stress response following trauma.

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.

Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study.

The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions.

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.