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.

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.

Emotional Changes during Imagery Rescripting of Aversive Social Memories in Social Anxiety Disorder: A Randomized Controlled Trial.

INTRODUCTION: Imagery rescripting (ImRs) is a psychotherapeutic intervention targeting aversive memories. During the three-phase intervention, patients reexperience their aversive memory (phase 1), observe the scene from their adult perspective, and intervene to help their former selves (phase 2), and reexperience it again with the positive changes (phase 3). Previous studies have rarely investigated emotional and regulatory processes taking place during the intervention. OBJECTIVE: This randomized controlled trial investigated self-reported affective and physiological responses during ImRs. METHODS: Seventy-seven patients with social anxiety disorder (SAD) were randomly assigned to a single session of ImRs or a control intervention (recall and discussion of the memory) targeting an aversive social memory. Heart rate (HR) and heart rate variability (HRV) were assessed during and post hoc ratings of positive and negative feelings after baseline and the intervention phases. RESULTS: Relative to the control intervention, ImRs resulted in an initial increase in negative feelings from baseline to phase 1 and a following larger (phase 1 to phase 2) and more stable (phase 2 to phase 3) decrease in negative feelings/increase in positive feelings. On the physiological level, during ImRs compared to the control intervention, mean HR was significantly higher during phase 1 and HRV during phase 3, each compared to baseline. CONCLUSIONS: These results provide further information about the specific sequence of emotional responses on different response levels during ImRs, being consistent with known theories of emotional processing and supposed mechanisms of ImRs.

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.

Love yourself as a therapist, doubt yourself as an institution? Therapist and institution effects on outcome, treatment length, and dropout.

OBJECTIVE: Research suggests that some therapists achieve better outcomes than others. However, an overlooked area of study is how institution differences impact patient outcomes independent of therapist variance. This study aimed to examine the role of institution and therapist differences in adult outpatient psychotherapy. METHOD: The study included 1428 patients who were treated by 196 therapists at 10 clinics. Two- and three-level hierarchical linear regression models were employed to investigate the effects of therapists and institutions on three dependent patient variables: (1) symptom change, (2) treatment duration, and (3) dropout. Level three explanatory variables were tested. RESULTS: The results showed that therapist effects (TE) were significant for all three types of treatment outcome (7.8%-18.2%). When a third level (institution) was added to the model, the differences between therapists decreased, and significant institution effects (IE) were found: 6.3% for symptom change, 10.6% for treatment duration, and 6.5% for dropout. The exploratory analyses found no predictors able to explain the systematic variation at the institution level. DISCUSSION: TE on psychotherapy outcomes remain a relevant factor but may have been overestimated in previous studies due to not properly distinguishing them from differences at the institution level.

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.

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.

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.

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.

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.

Brain structural connectivity and context-dependent extinction memory.

BACKGROUND: Extinction of conditioned fear represents an important mechanism in the treatment of anxiety disorders. Return of fear after successful extinction or exposure therapy in patients with anxiety disorders might be linked to poor temporal or contextual generalization of extinction due to individual differences in brain structural connectivity. The goal of this magnetic resonance imaging study was therefore to investigate the association of context-dependent extinction recall with brain structural connectivity. METHODS: Diffusion-tensor imaging was used to determine the fractional anisotropy as a measure of white matter structural integrity of fiber tracts connecting central brain regions of the fear and extinction circuit (uncinate fasciculus, cingulum). Forty-five healthy men participated in a two-day fear conditioning experiment with fear acquisition in context A and extinction learning in context B on the first day. Extinction recall in the extinction context as well as renewal in the acquisition context and a novel context C took place one day later. RESULTS: Renewal of conditioned fear (skin conductance responses) in the acquisition context was associated with higher structural integrity of the hippocampal part of the cingulum. CONCLUSIONS: Enhanced structural integrity of the cingulum might be related to stronger hippocampal modulation of the dorsal anterior cingulate cortex, a region important for modulating conditioned fear output by excitatory projections to the amygdala. This finding underpins the crucial role of individual differences in the structural integrity of relevant fiber tracts for context-dependent extinction recall and return of fear after exposure therapy in anxiety disorders.

Dispositional cognitive reappraisal modulates the neural correlates of fear acquisition and extinction.

Adverse learning experiences play a significant role in the etiology of anxiety disorders. However, not all individuals experiencing negative events develop heightened anxiety. This is possibly due to individual differences in the regulation of negative emotions associated with these negative events. Cognitive reappraisal is defined as reinterpreting an emotion-eliciting situation in a way that changes its emotional impact. A more frequent use of cognitive reappraisal in daily life has been shown to be more adaptive. However, no study to date examined the association of dispositional cognitive reappraisal with emotional learning, in order to elucidate individual differences in negative emotional responses towards aversive events. The goal of this functional magnetic resonance imaging (fMRI) study was to investigate the association of dispositional cognitive reappraisal with subjective, electrodermal and neural correlates of fear acquisition and extinction. Data of 41 healthy individuals, who participated in a socially relevant differential conditioning paradigm (acquisition and extinction learning: day 1, extinction recall: day 2), were acquired. Dispositional cognitive reappraisal was negatively associated with right insula, and hippocampus activation during acquisition. Furthermore, the reduction of self-reported conditioned fear during extinction learning as well as reduced insula and enhanced rostral anterior cingulate cortex activation during extinction learning was related to cognitive reappraisal. In addition, reduced recovery of conditioned arousal, reduced anterior cingulate and dorsomedial prefrontal cortex activation and enhanced ventromedial prefrontal cortex activation during extinction recall was observed in individuals with higher cognitive reappraisal scores. The results indicate that dispositional cognitive reappraisal modulates subjective and neural correlates of fear conditioning, probably leading to reduced acquisition and stronger extinction learning and recall. These results point to the important role of dispositional cognitive reappraisal in the development and modification of conditioned emotional responses and might further improve our understanding of anxiety disorders.

At the second glance: stability of neural responses toward visual sexual stimuli.

INTRODUCTION: Studies investigating the neural responses toward sexual stimuli can provide an important basis for further understanding disorders of sexual functioning. Although our knowledge of the neural correlates of sexual stimulus processing has increased considerably in the last decade, the stability of the observed effects in studies on neural sexual responses has been rather neglected. AIMS: The current study aimed to test the stability of behavioral and neural responses to visual sexual stimuli in men and women over a time span of 1 to 1.5 years. To disentangle valence and arousal-related aspects of sexual stimulus processing, we employed not only sexual and neutral, but also positive and negative emotional stimuli. METHODS: A sample of 56 subjects (24 women) was assessed twice, with an interval of 1 to 1.5 years between assessments. During a functional magnetic resonance imaging (fMRI) session, participants passively viewed sexual, neutral, positive, and negative emotional pictures. Pictures were presented in 24 blocks of five pictures each. Every block was rated immediately after its presentation with respect to valence, arousal, and sexual arousal. MAIN OUTCOME MEASURES: Blood oxygen level dependent (BOLD) responses measured by fMRI and stimulus ratings. RESULTS: fMRI analyses revealed a distributed network involved in the processing of sexual stimuli, with large parts of this network being consistently activated at both assessment points. Nucleus accumbens, anterior cingulate, occipital and parietal cortex showed the most robust results with respect to group stability. Responses of anterior cingulate, orbitofrontal, parietal and occipital cortex showed interindividual stability. Gender differences were restricted to a few regions of interest. CONCLUSIONS: Our data indicate stability of neural responses toward sexual stimuli not only on the group but also on the individual level. Activation of parietal and occipital cortex might reflect a trait like character of attention related responses toward sexual stimuli.

Gender commonalities and differences in the neural processing of visual sexual stimuli.

INTRODUCTION: Few studies so far have directly compared the neural processing of visual sexual stimuli in men and women. Also, most of these studies only compared sexual with neutral stimuli, making it difficult to disentangle sexual stimulus processing from general emotional processing. AIM: The current study aimed to explore gender commonalities and differences in neural activity associated with the processing of visual sexual stimuli in a large sample of 50 men and 50 women. In order to disentangle effects of sexual processing from those of general emotional processing, we employed sexual, neutral, positive, and negative emotional pictures. METHODS: Subjects passively viewed sexual, neutral, positive, and negative emotional pictures during a functional magnetic resonance imaging (fMRI) session. Pictures were presented in 24 blocks of five pictures each. Every block was rated immediately after its presentation with respect to valence, arousal, and sexual arousal. MAIN OUTCOME MEASURES: Blood oxygen level dependent responses measured by fMRI and subjective ratings. RESULTS: fMRI analysis revealed a distributed network for the neural processing of sexual stimuli comprising the hypothalamus, the nucleus accumbens, as well as orbitofrontal, occipital, and parietal areas. This network could be identified (i) for both men and women, with men showing overall stronger activations than women and (ii) independent of general emotional arousal or valence effects. CONCLUSION: Our data speak in favor of a common neural network associated with the processing of visual sexual stimuli in men and women. Apart from the observed gender commonalities, overall stronger responses in men were observed that might indicate stronger sexual responsivity in men.

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.

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.

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.

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.

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.

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.