Decontextualized fear memories? Stronger conditioned fear responses during extinction learning and extinction recall in a safe context predict the development of long-term analog intrusions.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Neural correlates of context-dependent extinction recall in social anxiety disorder: relevance of intrusions in response to aversive social experiences.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Neural correlates of immediate versus delayed extinction when simultaneously varying the time of the test in humans.

Anxiety disorders are effectively treated with exposure therapy based on the extinction of Pavlovian fear conditioning. Animal research indicates that both the timing of extinction and test are important factors to reduce the return of fear. However, empirical evidence in humans is incomplete and inconsistent. In this neuroimaging study, we, therefore, tested 103 young, healthy participants in a 2-factorial between-subjects design with the factors extinction group (immediate, delayed) and test group (+1 day and +7 days). Immediate extinction led to greater retention of fear memory at the beginning of extinction training indicated by increased skin conductance responses. A return of fear was observed in both extinction groups, with a trend toward a greater return of fear in immediate extinction. The return of fear was generally higher in groups with an early test. Neuroimaging results show successful cross-group fear acquisition and retention, as well as activation of the left nucleus accumbens during extinction training. Importantly, the delayed extinction group showed a larger bilateral nucleus accumbens activation during test. This nucleus accumbens finding is discussed in terms of salience, contingency, relief, and prediction error processing. It may imply that the delayed extinction group benefits more from the test as a new learning opportunity.

Weathering the storm of emotions: immediate and lasting effects of reinterpretation and distancing on event-related potentials and their association with habitual use of cognitive reappraisal.

Reinterpretation and distancing, two cognitive reappraisal tactics, are known to effectively reduce negative feelings and event-related potentials (ERPs), such as the P300 and the late positive potential (LPP), in the short-term. Less is known about differential and lasting effects on ERPs as well as their association with habitual reappraisal. Fifty-seven participants were instructed to passively view or reappraise (reinterpretation, distancing) pictures that were repeatedly presented with the same instruction (active regulation phase). Thirty minutes later, these pictures were shown again without instruction for the assessment of lasting effects (re-exposure phase). ERPs were recorded and participants rated the intensity of negative feelings following picture presentation. Reappraisal led to an attenuation of the LPP, and both tactics decreased negative feelings during active regulation, whereby reinterpretation had a stronger impact on the subjective level. Passive re-exposure resulted in reduced negative feelings for previously reappraised pictures but had no lasting effects on ERPs. Higher habitual reappraisal was associated with higher P300 and early LPP amplitudes for emotional reactivity during the active regulation phase. During the re-exposure phase, higher habitual reappraisal was not related to ERPs. The current findings emphasize the effectiveness of both tactics in the short-term and lasting effects on the subjective experience of negative feelings. Enhanced emotional reactivity on the electrocortical level in individuals with a more frequent habitual use of reappraisal might indicate a higher preparedness to regulate.

Behavioral pattern separation is associated with neural and electrodermal correlates of context-dependent fear conditioning.

Hippocampus-dependent pattern separation is considered as a relevant factor for context discrimination and might therefore impact the contextual modulation of conditioned fear. However, the association between pattern separation and context-dependent fear conditioning has not been investigated so far. In the current study, 72 healthy female students completed the Mnemonic Similarity Task, a measure of behavioral pattern separation, in addition to a context-dependent fear conditioning paradigm during functional magnetic resonance imaging. The paradigm included fear acquisition in context A and extinction training in context B on a first day, as well as retrieval testing of the fear and extinction memories in the safe context B (extinction recall) and a novel context C (fear renewal) one day later. Main outcome measures comprised skin conductance responses (SCRs) and blood oxygen level-dependent responses in brain regions of the fear and extinction circuit. Regarding retrieval testing, pattern separation did not correlate with extinction recall, but with stronger dorsal anterior cingulate cortex activation and conditioned SCRs (trend) during fear renewal, indicating a stronger retrieval of the fear memory trace. Our findings suggest that behavioral pattern separation ability seems to be important for context-dependent fear modulation, which is impaired in patients with posttraumatic stress disorder.

The importance of high quality real-life social interactions during the COVID-19 pandemic.

The coronavirus pandemic has brought about dramatic restrictions to real-life social interactions and a shift towards more online social encounters. Positive social interactions have been highlighted as an important protective factor, with previous studies suggesting an involvement of the amygdala in the relationship between social embeddedness and well-being. The present study investigated the effect of the quality of real-life and online social interactions on mood, and explored whether this association is affected by an individual's amygdala activity. Sixty-two participants of a longitudinal study took part in a one-week ecological momentary assessment (EMA) during the first lockdown, reporting their momentary well-being and their engagement in real-life and online social interactions eight times per day (N ~ 3000 observations). Amygdala activity was assessed before the pandemic during an emotion-processing task. Mixed models were calculated to estimate the association between social interactions and well-being, including two-way interactions to test for the moderating effect of amygdala activity. We found a positive relationship between real-life interactions and momentary well-being. In contrast, online interactions had no effect on well-being. Moreover, positive real-life social interactions augmented this social affective benefit, especially in individuals with higher amygdala being more sensitive to the interaction quality. Our findings demonstrate a mood-lifting effect of positive real-life social interactions during the pandemic, which was dependent on amygdala activity before the pandemic. As no corresponding effect was found between online social interactions and well-being, it can be concluded that increased online social interactions may not compensate for the absence of real-life social interactions.

Memory representation of aversive social experiences in Social Anxiety Disorder.

Aversive social experiences are proposed to be a risk factor for developing Social Anxiety Disorder (SAD). Many patients with SAD report associated daily life symptoms, such as intrusive re-experiencing (e.g., negatively distorted images of oneself), avoidance, alterations in cognitions and mood, as well as hyperarousal, resembling symptom dimensions of Posttraumatic Stress Disorder (PTSD). These PTSD-like symptoms may result from maladaptive processing and representation of the aversive social experiences in memory. Emotional hyperreactivity during memory retrieval of aversive social experiences is another feature of SAD which was found in previous studies. This study aimed to further investigate PTSD-like symptoms and emotional reactivity associated with etiologically relevant aversive social experiences and shed more light on a potential relationship between both. Eighty-five patients with SAD and 85 healthy controls (HC) participated in this cross-sectional study. It comprised an imagination task with self-report and physiological measures to assess emotional reactivity during the cued recall of the aversive social experience and clinical interviews to assess PTSD-like symptoms. We expected increased emotional reactivity and more severe PTSD-like symptoms in response to the aversive social experience in patients with SAD compared to HC, as well as a positive correlation between emotional reactivity and PTSD-like symptoms in patients with SAD. Indeed, patients with SAD showed emotional hyperreactivity (self-report, physiology) during the cued recall of the aversive social experiences, also when compared to two control memory conditions (neutral, negative non-social) and HC. Patients with SAD furthermore reported more severe PTSD-like symptoms compared to HC and intrusive re-experiencing symptoms were positively correlated with distress during imagery of the social aversive event in patients with SAD. These results might point toward a maladaptive representation of aversive social experiences in memory. Similar to PTSD, this maladaptive memory representation might promote the development of PTSD-like symptoms such as intrusive re-experiencing (e.g., in the form of intrusive self-images in patients with SAD), which might finally lead to and maintain symptoms of SAD.

ß-Endorphin mediates radiation therapy fatigue.

Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. ß-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as ß-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived ß-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma ß-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either ß-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived ß-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.

Prefrontal-amygdala emotion regulation and depression in multiple sclerosis.

Depression is among the most common comorbidities in multiple sclerosis and has severe psychosocial consequences. Alterations in neural emotion regulation in amygdala and prefrontal cortex have been recognized as key mechanism of depression but never been investigated in multiple sclerosis depression. In this cross-sectional observational study, we employed a functional MRI task investigating neural emotion regulation by contrasting regulated versus unregulated negative stimulus perception in 16 persons with multiple sclerosis and depression (47.9 ± 11.8 years; 14 female) and 26 persons with multiple sclerosis but without depression (47.3 ± 11.7 years; 14 female). We tested the impact of depression and its interaction with lesions in amygdala-prefrontal fibre tracts on brain activity reflecting emotion regulation. A potential impact of sex, age, information processing speed, disease duration, overall lesion load, grey matter fraction, and treatment was taken into account in these analyses. Patients with depression were less able (i) to downregulate negative emotions than those without (t = -2.25, P = 0.012, ß = -0.33) on a behavioural level according to self-report data and (ii) to downregulate activity in a left amygdala coordinate (t = 3.03, P Family-wise error [FWE]-corrected = 0.017, ß = 0.39). Moreover, (iii) an interdependent effect of depression and lesions in amygdala-prefrontal tracts on activity was found in two left amygdala coordinates (t = 3.53, pFWE = 0.007, ß = 0.48; t = 3.21, pFWE = 0.0158, ß = 0.49) and one right amygdala coordinate (t = 3.41, pFWE = 0.009, ß = 0.51). Compatible with key elements of the cognitive depression theory formulated for idiopathic depression, our study demonstrates that depression in multiple sclerosis is characterized by impaired neurobehavioural emotion regulation. Complementing these findings, it shows that the relation between neural emotion regulation and depression is affected by lesion load, a key pathological feature of multiple sclerosis, located in amygdala-prefrontal tracts.

Social phobic beliefs mediate the relationship between post-event processing regarding the worst socially aversive experience and fear of negative evaluation.

The experience of socially aversive events is proposed to be a critical etiological factor in the development of social anxiety symptoms even though the experience itself is also common among healthy individuals. Rather than the event itself, accompanying factors such as maladaptive processing might be associated with higher levels of social anxiety symptoms. One-hundred-seventy-four individuals participated in this online-survey comprising questionnaires regarding social anxiety symptoms and retrospective reports concerning maladaptive processing of the worst socially aversive event. Structural equation modelling was used to analyze the hypothesized mediation of maladaptive processing and fear of negative evaluation by intrusive re-experiencing and social phobic beliefs. The positive association between retrospectively evaluated maladaptive processing after the worst socially aversive event and fear of negative evaluation was mediated by social phobic beliefs but not by intrusive re-experiencing. These results point towards the relevance of further investigating processing strategies after socially aversive events as a potential influencing factor for SAD development. Trial registration. The trial was registered at the German Clinical Trial Register (DRKS00021502) on June 3rd, 2020. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12144-022-02805-9.

Coping under stress: Prefrontal control predicts stress burden during the COVID-19 crisis.

The coronavirus (COVID-19) pandemic has confronted millions of people around the world with an unprecedented stressor, affecting physical and mental health. Accumulating evidence suggests that emotional and cognitive self-regulation is particularly needed to effectively cope with stress. Therefore, we investigated the predictive value of affective and inhibitory prefrontal control for stress burden during the COVID-19 crisis. Physical and mental health burden were assessed using an online survey, which was administered to 104 participants of an ongoing at-risk birth cohort during the first wave in April 2020. Two follow-ups were carried out during the pandemic, one capturing the relaxation during summer and the other the beginning of the second wave of the crisis. Prefrontal activity during emotion regulation and inhibitory control were assessed prior to the COVID-19 crisis. Increased inferior frontal gyrus activity during emotion regulation predicted lower stress burden at the beginning of the first and the second wave of the crisis. In contrast, inferior and middle frontal gyrus activity during inhibitory control predicted effective coping only during the summer, when infection rates decreased but stress burden remained unchanged. These findings remained significant when controlling for sociodemographic and clinical confounders such as stressful life events prior to the crisis or current psychopathology. We demonstrate that differential stress-buffering effects are predicted by the neural underpinnings of emotion regulation and cognitive regulation at different stages during the pandemic. These findings may inform future prevention strategies to foster stress coping in unforeseen situations.

Vitamin D deficiency exacerbates UV/endorphin and opioid addiction.

The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.

Reduced MC4R signaling alters nociceptive thresholds associated with red hair.

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.

Lasting effects of cognitive emotion regulation: neural correlates of reinterpretation and distancing.

Reinterpretation and distancing are two cognitive reappraisal tactics, used to regulate one's emotions in response to emotion-eliciting stimuli or situations. Relatively less is known about their (differential) lasting effects on emotional responding and related neural correlates. This functional magnetic resonance imaging study investigated 85 healthy females, participating in a 2-day cognitive emotion regulation experiment. On the first day, participants were instructed to passively look at, reinterpret or distance from repeatedly presented aversive pictures. One week later, they were re-exposed to the same stimuli without regulation instruction, in order to assess lasting effects. The main outcome measures comprised ratings of negative feelings and blood-oxygen-level-dependent responses. Lasting effects for reinterpretation compared with looking at aversive pictures during passive re-exposure 1 week later were reflected in stronger activation of the left amygdala, the ventromedial prefrontal cortex (vmPFC) and reduced negative feelings. Neither distancing compared with looking at aversive pictures nor reinterpretation compared with distancing did result in significant effects during re-exposure. These findings indicate that reinterpretation leads to reduced negative feelings 1 week later, which might be mediated by inhibitory vmPFC activation or stronger positive emotions during re-exposure. However, the missing difference compared with distancing questions the specificity of the results and the mechanisms underlying these two cognitive reappraisal tactics.

Trauma-focused psychodynamic therapy and STAIR Narrative Therapy of post-traumatic stress disorder related to childhood maltreatment: trial protocol of a multicentre randomised controlled trial assessing psychological, neurobiological and health economic outcomes (ENHANCE).

INTRODUCTION: Success rates of psychotherapy in post-traumatic stress disorder related to childhood maltreatment (PTSD-CM) are limited. METHODS AND ANALYSIS: Observer-blind multicentre randomised clinical trial (A-1) of 4-year duration comparing enhanced methods of STAIR Narrative Therapy (SNT) and of trauma-focused psychodynamic therapy (TF-PDT) each of up to 24 sessions with each other and a minimal attention waiting list in PTSD-CM. Primary outcome is severity of PTSD (Clinician-Administered PTSD Scale for DSM-5 total) assessed by masked raters. For SNT and TF-PDT, both superiority and non-inferiority will be tested. Intention-to-treat analysis (primary) and per-protocol analysis (secondary). Assessments at baseline, after 10 sessions, post-therapy/waiting period and at 6 and 12 months of follow-up. Adult patients of all sexes between 18 and 65 years with PTSD-CM will be included. Continuing stable medication is permitted. To be excluded: psychotic disorders, risk of suicide, ongoing abuse, acute substance related disorder, borderline personality disorder, dissociative identity disorder, organic mental disorder, severe medical conditions and concurrent psychotherapy. To be assessed for eligibility: n=600 patients, to be e randomly allocated to the study conditions: n=328. Data management, randomisation and monitoring will be performed by an independent European Clinical Research Infrastructure Network (ECRIN)-certified data coordinating centre for clinical trials (KKS Marburg). Report of AEs to a data monitoring and safety board. Complementing study A-1, four inter-related add-on projects, including subsamples of the treatment study A-1, will examine (1) treatment integrity (adherence and competence) and moderators and mediators of outcome (B-1); (2) biological parameters (B-2, eg, DNA damage, reactive oxygen species and telomere shortening); (3) structural and functional neural changes by neuroimaging (B-3) and (4) cost-effectiveness of the treatments (B-4, costs and utilities). ETHICS AND DISSEMINATION: Approval by the institutional review board of the University of Giessen (AZ 168/19). Following the Consolidated Standards of Reporting Trials statement for non-pharmacological trials, results will be reported in peer-reviewed scientific journals and disseminated to patient organisations and media. TRIAL REGISTRATION NUMBER: DRKS 00021142.

Females' menstrual cycle and incentive salience: Insights on neural reaction towards erotic pictures and effects of gonadal hormones.

Background: Studies in regard to womens' neural reactivity to erotic and other positive emotional cues in association with sexual hormones are relatively rare and findings rather inconclusive. Concerning the neural reactions towards erotic stimuli, the late positive potential (LPP) is seen as the most relevant ERP-component: More positive amplitudes are supposed to reflect larger motivational salience and higher arousal in reaction to the presented stimuli. Therefore, it was expected that the LPP in reaction to erotic pictures would be more pronounced during fertile periods of the menstrual cycle around ovulation, as well as to be associated with estradiol-levels. A similar pattern was hypothesized to be present with testosterone-levels, whereas no association with progesterone was expected. Method: N â€‹= â€‹35 free-cycling women completed an Erotic picture Stroop task (neutral, positive, and erotic stimuli, with three neutral- and three erotic subcategories) during follicular phase, ovulation and luteal phase, while EEG was recorded. Subjects provided saliva samples in order to determine estradiol-, progesterone-, and testosterone levels at each measuring time, and affective states were assessed using the Positive and Negative Affect Scale (PANAS). Results: LPPs in reaction to erotic-compared to positive- and neutral pictures were larger in every cycle phase. LPPs in reaction to erotic couples were strongest in comparison to every other (sub-) category. During ovulation, higher estradiol-concentrations were associated with lower LPP-amplitudes towards erotic-couples- than to neutral pictures. No effects of progesterone, no direct effect of testosterone, as well as no effects of cycle phase, were evident. Conclusion: Results partly contradict our hypotheses, as estradiol was expected to be positively associated with LPP during fertile stages. Possible differences between stimulus-entities (words v. pictures) and ideas for further research are being discussed.

Multiple extinction contexts modulate the neural correlates of context-dependent extinction learning and retrieval.

Exposure therapy is a successful treatment for patients with anxiety and fear-related disorders. Extinction of conditioned fear comprises one important mechanism underlying the effects of exposure therapy. Yet, relapses frequently occur in the long-term, probably related to difficulties in generalizing the extinction of conditioned fear to new contexts, leading to renewal of conditioned fear. Extinction training in multiple extinction contexts depicts a promising opportunity to reduce this renewal of conditioned fear. However, the underlying neural correlates are unknown yet. In this functional magnetic resonance imaging study, 49 healthy men participated in a fear conditioning paradigm with fear acquisition training in context A on a first day, extinction training in a single context (B1) or in four different contexts (B1-B4) one day later, and fear and extinction recall and reinstatement in context B1 and a novel context C on a third day one week later. Multiple extinction contexts led to a stronger differential activation decrease in the hippocampus during extinction learning compared to a single extinction context. One week later, the multiple context group compared with the single context group showed reduced differential amygdala activation during fear renewal in the novel context C compared with the extinction context B1. Furthermore, multiple extinction contexts diminished amygdala activation during a subsequent reinstatement test in context B1. However, there were no significant differences in differential conditioned SCRs. These results indicate that the use of multiple extinction contexts during extinction training leads to reduced conditioned responses in the amygdala-hippocampus complex.

Cognitive Behaviour Therapy Complemented with Emotion Regulation Training for Patients with Persistent Physical Symptoms: A Randomised Clinical Trial.

INTRODUCTION: Persistent medically unexplained symptoms (MUS) are a major burden for health care. Cognitive behaviour therapy (CBT) is efficacious for patients with MUS, with small to medium effects. The current study investigates whether therapy outcomes of a CBT for MUS patients can be improved by complementing it with emotion regulation training. METHODS: In a multicentre trial 255 patients with at least three persisting MUS were randomised to 20 sessions of either conventional CBT (n = 128) or CBT complemented with emotion regulation training (ENCERT; n = 127). Somatic symptom severity and secondary outcomes were assessed at pre-treatment, therapy session 8, end of therapy, and 6-month follow-up. RESULTS: Linear mixed-effect models revealed medium to large effects in both study arms for almost all outcomes at the end of therapy and 6-month follow-up. ENCERT and CBT did not differ in their effect on the primary outcome (d = 0.20, 95% CI: -0.04 to 0.44). Significant time × group cross-level interactions suggested ENCERT to be of more benefit than conventional CBT for a few secondary outcomes. Moderator analyses revealed higher effects of ENCERT in patients with co-morbid mental disorders. DISCUSSION/CONCLUSIONS: Current findings are based on a representative sample. Results demonstrate that both CBT and ENCERT can achieve strong effects on primary and secondary outcomes in MUS patients. Our results do not indicate that adding a training in emotion regulation skills generally improves the effect of CBT across all patients with MUS. Large effect sizes of both treatments and potential specific benefits of ENCERT for patients with co-morbid mental disorders are discussed.

Fear Extinction Recall Modulates Human Frontomedial Theta and Amygdala Activity.

Human functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) studies, as well as animal studies, indicate that the amygdala and frontomedial brain regions are critically involved in conditioned fear and that frontomedial oscillations in the theta range (4-8 Hz) may support communication between these brain regions. However, few studies have used a multimodal approach to probe interactions among these key regions in humans. Here, our goal was to bridge the gap between prior human fMRI, EEG, and animal findings. Using simultaneous EEG-fMRI recordings 24 h after fear conditioning and extinction, conditioned stimuli presented (CS+E, CS-E) and not presented during extinction (CS+N, CS-N) were compared to identify effects specific to extinction versus fear recall. Differential (CS+ vs. CS-) electrodermal, frontomedial theta (EEG) and amygdala responses (fMRI) were reduced for extinguished versus nonextinguished stimuli. Importantly, effects on theta power covaried with effects on amygdala activation. Fear and extinction recall as indicated by theta explained 60% of the variance for the analogous effect in the right amygdala. Our findings show for the first time the interplay of amygdala and frontomedial theta activity during fear and extinction recall in humans and provide insight into neural circuits consistently linked with top-down amygdala modulation in rodents.

Orthorexia nervosa: A behavioral complex or a psychological condition?

BACKGROUND AND AIMS: Numerous studies have provided evidence for orthorexia nervosa (ON), an eating pattern characterized by an almost manic obsession for and fixation on healthy eating, to be of epidemiological relevance. However, there is scientific debate on whether it is merely a behavioral or lifestyle phenomenon as compared to a mental disorder. Aim of this cross-sectional study was to explore whether ON is of epidemiological and clinical relevance, and whether ON can be distinguished from other mental health disorders and healthy lifestyle features. METHODS: An online survey including a measure of orthorexic behaviors [Duesseldorf Orthorexia Scale (DOS)], well-being and distress, eating behaviors, pathological eating, anxiety and depression, addictive behaviors, obsessive-compulsive symptoms, personality, and health behaviors was completed by 713 subjects (79.8% women, 18-75 years, median age: 25 years). RESULTS: Twenty-seven subjects (3.8%, 21 women) showed significant orthorexic eating (DOS ≥ 30). ON cases reported lower well-being, lower satisfaction with life, and higher current stress levels than non-ON cases. The highest percentage of variation in ON was explained by pathological eating (R2 = .380), followed by eating style, Mediterranean diet, compulsive symptoms, and subjective social status. Importantly, ON provided hardly any additional predictive value for well-being when also considering pathological eating. DISCUSSION AND CONCLUSIONS: Our data confirmed the epidemiological and clinical relevance of orthorexic behaviors, but the strong conceptual overlap with other mental health problems and pathological eating raise initial doubts as to whether ON is a distinct mental health disorder category. This co-occurrence, unique symptoms, and underlying processes need further exploration by comparing ON cases with patients with other mental disorders.