What time-varying network models based on functional analysis tell us about the course of a patient's problem.

Background: Relations among psychological variables are assumed to be complex and to vary over time. Personalized networks can model multivariate complex interactions. The development of time-varying networks allows to model the variation of parameters over time. Objectives: We aimed to determine the value of time-varying networks for clinical practice. Methods: We applied time-varying mixed graphical models (TV-MGM) and time-varying vector autoregressive models (TV-VAR) to intensive longitudinal data of nine participants with depressive symptoms (n = 6) or anxiety (n = 3). Results: Most of the participants showed temporal changes in network topology within the assessment period of 30 days. Time-varying networks of participants with small, medium, and large time variability in edge parameters clearly show the different temporal evolvements of dynamic interactions between variables. The case example indicates clinical utility but also limitations to the application of time-varying networks in clinical practice. Conclusion: Time-varying network models provide a data-driven and exploratory approach that could complement current diagnostic standards by reflecting interacting, often mutually reinforcing processes of mental health problems and by accounting for variation over time. They can be used to generate hypotheses for further confirmatory and clinical testing.

Originalarbeiten / Original Articles. Entwicklung und Evaluation einer Aufklärungsbroschüre zu Ängsten und Angststörungen für Jugendliche.

Development and Evaluation of an Information Brochure on Anxiety and Anxiety Disorders for Adolescents Low mental health literacy and fear of being stigmatized are two main barriers that detain adolescents fromseeking professional help. An information brochure about anxiety disorders for adolescents was developed. To make a first statement about the quality of the brochure, 19 experts, consisting of (child and adolescents) psychotherapists, psychiatrists, and psychologists, rated a first version of the brochure regarding content validity and age-appropriatness. To evaluate the efficacy in knowledge and the acceptance of the brochure, a revised version was evaluated by N = 174 adolscents (106 female-, 66 male- and two non-binary) between 14 and 17 years of age (M = 16.56 years.; SD = 0.57).The experts' approval of all content items totals a mean average of 95.2 % (range: 84.2-100 %). In the adolescent sample, the intervention increased knowledge about anxiety disorders (d = 1.04) and improved attitudes about coping strategies (d = 0.99). Results of the experts' rating showed that content validity of the brochure can be assumed.The revised brochure seems to be a useful and effective tool to inform adolescents about anxiety disorders.

Psychological Factors Predict Higher Odds and Impairment of Post-COVID Symptoms: A Prospective Study.

OBJECTIVE: The causes of the long-term persistence of symptoms after a severe acute respiratory syndrome coronavirus 2 infection (i.e., post-COVID syndrome) remain elusive. Although previous research identified demographic and medical risk factors for the development of post-COVID, the present prospective study is the first to investigate the role of psychological factors. METHODS: The interview and survey data of polymerase chain reaction-positive participants ( n = 137; 70.8% female) were assessed in the acute, subacute (3 months after symptom onset), and chronic phases (6 months after symptom onset) of COVID. RESULTS: After controlling for medical (body mass index, disease score) and demographic factors (sex, age), psychosomatic symptom burden (measured by the Somatic Symptom Disorder-B Criteria Scale) predicted higher odds and magnitude of COVID-related symptom impairment in the post-COVID phases. Fear of COVID-related health consequences (measured by the Fear of COVID Scale) also predicted higher odds of reporting any COVID symptoms in the subacute and chronic phases, whereas it only predicted a higher magnitude of COVID-related symptom impairment in the subacute phase. In subsequent exploratory analyses, we found that other psychological factors were associated with an overall increase (i.e., chronic stress and depression) or decrease (i.e., trait positive affect) in the odds and magnitude of COVID-related symptom impairment. CONCLUSIONS: We conclude that psychological factors can fuel or temper the experience in post-COVID syndrome, opening new possibilities for psychological interventions. TRIAL REGISTRATION: The study protocol was preregistered in the Open Science Framework ( https://osf.io/k9j7t ).

Feeling lonely during the pandemic: Towards personality-tailored risk profiles.

This is the first study to disentangle associations of within- and between-person fluctuations in loneliness and their effect on evening mood during a nationwide lockdown due to COVID-19. To contribute to the development of personality-tailored risk profiles, we additionally explored the moderating role of trait neuroticism and extraversion on the association of within- and between-person loneliness and mood. We employed an ambulatory assessment design during 21 days of nationwide lockdown in Germany (13/04/2020-03/05/2020) with two interval-based assessments. The final sample comprised 322 participants (74.5% women) aged between 15 and 82 years (M = 30.7, SD = 14.9) providing 6,084 evening assessments. Linear mixed models were used to evaluate the effects of within- and between-person fluctuations in loneliness on evening mood while controlling for unspecific effects of time, sex, and age. Moderation analysis was used to investigate the influence of neuroticism and extraversion on the relation between loneliness and mood, respectively. Results indicate that especially higher between-person loneliness (i.e. participants felt lonelier compared to the average participant) but also higher within-person loneliness (i.e. participants felt lonelier compared to their individual mean) were associated with a more unpleasant mood. Neuroticism augmented the effect of within-person loneliness, while extraversion seemed to buffer the effect of between-person loneliness on mood. Our findings underline the importance of carefully monitoring loneliness during COVID-19. The findings contribute towards the development of personality-tailored risk profiles (e.g. among newly arising risk groups for loneliness due to COVID-19). We discuss how the differential consideration of within- and between-psychological processes might help to elucidate currently mixed findings on psychological coping during the COVID-19 pandemic.

Does Active Inference Provide a Comprehensive Theory of Placebo Analgesia?

Placebo interventions generate mismatches between expected pain and sensory signals from which pain states are inferred. Because we lack direct access to bodily states, we can only infer whether nociceptive activity indicates tissue damage or results from noise in sensory channels. Predictive processing models propose to make optimal inferences using prior knowledge given noisy sensory data. However, these models do not provide a satisfactory explanation of how pain relief expectations are translated into physiological manifestations of placebo responses. Furthermore, they do not account for individual differences in the ability to endogenously regulate nociceptive activity in predicting placebo analgesia. The brain not only passively integrates prior pain expectations with nociceptive activity to infer pain states (perceptual inference) but also initiates various types of actions to ensure that sensory data are consistent with prior pain expectations (active inference). We argue that depending on whether the brain interprets conflicting sensory data (prediction errors) as a signal to learn from or noise to be attenuated, the brain initiates opposing types of action to facilitate learning from sensory data or, conversely, to enhance the biasing influence of prior pain expectations on pain perception. Furthermore, we discuss the role of stress, anxiety, and unpredictability of pain in influencing the weighting of prior pain expectations and sensory data and how they relate to the individual ability to regulate nociceptive activity (endogenous pain modulation). Finally, we provide suggestions for future studies to test the implications of the active inference model of placebo analgesia.

Change in pain expectations but no open-label placebo analgesia: An experimental study using the heat pain paradigm.

BACKGROUND: Open-label placebos (OLP) prescribed without deception and with a convincing rationale have been shown to evoke powerful treatment effects. Patients' treatment expectations seem to influence the magnitude of the effect. OBJECTIVE: We examined if two different OLP rationales increased pain tolerance and reduced pain intensity and unpleasantness in a standardized heat pain experiment. METHODS: Participants (N = 71) who self-reported reoccurring pain for at least the last 3 months were randomly assigned to one of three groups. We compared a personal-emotional and a scientific-matter-of-fact rationale with a control group (CG) that received the same placebo without any rationale. The rationale suggested a desensitizing effect on pain perception and improved pain coping of the placebo, whereas in the CG it was introduced as an ointment for measurement. The primary outcomes were pre-post changes in pain tolerance, expected and experienced pain intensity and unpleasantness. RESULTS: Participants showed a decrease in expected pain intensity, but not expected pain unpleasantness for both rationales. There were no differences in pain tolerance and experienced pain intensity and unpleasantness. CONCLUSIONS: Our study suggests that evoking positive treatment expectations is not sufficient to elicit an OLP response. Possibly, the magnitude of expectations change in this study was not powerful enough to evoke an OLP effect. Additionally, it is possible that OLP effects in pain are unrelated to positive treatment expectations. The failure of OLP in our study is in contrast to a number of previous studies examining the effects of OLP in experimental and clinical pain. SIGNIFICANCE: This study provides evidence that positive treatment expectations are not sufficient to evoke an open-label placebo effect in a standardized heat pain experiment. We showed that two different rationales improved participants treatment expectations, but failed to evoke a placebo effect in comparison to a control group that received the same placebo, labelled as an ointment to improve measurement quality.

Metacognitive therapy versus exposure and response prevention for obsessive-compulsive disorder - A non-inferiority randomized controlled trial.

OBJECTIVE: Exposure with response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD). However, refusals, dropouts and the required high time and logistic effort constitute barriers to the use of ERP. In a non-inferiority randomized controlled trial, we compared metacognitive therapy (MCT) to exposure with response prevention (ERP) as treatments for OCD. METHOD: 74 outpatients received 12 weekly sessions of either manualized MCT or ERP, with primary outcomes assessed by blinded assessors using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at pre-treatment, mid-treatment, post-treatment, and 6-month follow-up. Secondary outcomes included measures of depression and anxiety. Non-inferiority margin was specified at no less than d = 0.38 below the improvement reached by ERP, corresponding to a difference of about 3 points on the Y-BOCS. RESULTS: Drop-out rates were low (<14%) and similar in both groups. Linear models indicated non-inferiority of MCT to ERP at post-treatment, but not at 6-month follow-up. While both groups showed comparable Y-BOCS improvements, the MCT group demonstrated a significantly greater reduction in state anxiety scores at post-treatment and follow-up. CONCLUSIONS: Overall, MCT was not inferior to ERP, especially at post-treatment, suggesting it could be a treatment alternative. However, further research is needed to explore differential treatment indications.

Digital Health Apps in the Context of Dementia: Questionnaire Study to Assess the Likelihood of Use Among Physicians.

BACKGROUND: Age-related diseases such as dementia are playing an increasingly important role in global population development. Thus, prevention, diagnostics, and interventions require more accessibility, which can be realized through digital health apps. With the app on prescription, Germany made history by being the first country worldwide to offer physicians the possibility to prescribe and reimburse digital health apps as of the end of the year 2020. OBJECTIVE: Considering the lack of knowledge about correlations with the likelihood of use among physicians, this study aimed to address the question of what makes the use of a digital health app by physicians more likely. METHODS: We developed and validated a novel measurement tool-the Digital Health Compliance Questionnaire (DHCQ)-in an interdisciplinary collaboration of experts to assess the role of proposed factors in the likelihood of using a health app. Therefore, a web-based survey was conducted to evaluate the likelihood of using a digital app called DemPredict to screen for Alzheimer dementia. Within this survey, 5 latent dimensions (acceptance, attitude toward technology, technology experience, payment for time of use, and effort of collection), the dependent variable likelihood of use, and answers to exploratory questions were recorded and tested within directed correlations. Following a non-probability-sampling strategy, the study was completed by 331 physicians from Germany in the German language, of whom 301 (90.9%) fulfilled the study criteria (eg, being in regular contact with patients with dementia). These data were analyzed using a range of statistical methods to validate the dimensions of the DHCQ. RESULTS: The DHCQ revealed good test theoretical measures-it showed excellent fit indexes (Tucker-Lewis index=0.98; comparative fit index=0.982; standardized root mean square residual=0.073; root mean square error of approximation=0.037), good internal consistency (Cronbach α=.83), and signs of moderate to large correlations between the DHCQ dimensions and the dependent variable. The correlations between the variables acceptance, attitude toward technology, technology experience, and payment for the time of use and the dependent variable likelihood of use ranged from 0.29 to 0.79, and the correlation between effort of the collection and likelihood of use was -0.80. In addition, we found high levels of skepticism regarding data protection, and the age of the participants was found to be negatively related to their technical experience and attitude toward technology. CONCLUSIONS: In the context of the results, increased communication between the medical and technology sectors and significantly more awareness raising are recommended to make the use of digital health apps more attractive to physicians as they can be adjusted to their everyday needs. Further research could explore the connection between areas such as adherence on the patient side and its impact on the likelihood of use by physicians.

The Prevalence and Characteristics of Phantom Limb Pain and Non-Painful Phantom Phenomena in a Nationwide Survey of 3,374 Unilateral Limb Amputees.

The experience of phantom limb pain (PLP) is a common consequence of limb amputation, resulting in severe impairments of the affected person. Previous studies have shown that several factors such as age at or site of amputation are associated with the emergence and maintenance of PLP. In this cross-sectional study we assessed the presence of several phantom phenomena including PLP and other amputation-related information in a sample of 3,374 unilateral upper and lower limb amputees. Clinical and demographic variables (age at amputation, level of amputation) explained 10.6% of the variance in PLP and perceptual variables (intensity of phantom limb sensation [PLS], referred sensations, intensity of telescoping, residual limb pain [RLP] intensity) explained 16.9% of the variance. These variables were specific for PLP and not for RLP. These results suggest that distinct variables are associated with PLP (age at amputation, level of amputation, PLS intensity, referred sensations, intensity of telescoping, RLP intensity) and RLP (PLP intensity) and point at partly different mechanisms for the emergence and maintenance of PLP and RLP. PERSPECTIVE: Clinical/demographic variables as well as perceptual variables are 2 major components related to PLP and explain ∼11% and ∼17% of the variance. These results could potentially help clinicians to understand which factors may contribute to chronic phantom limb pain.

Phantom limb pain after unilateral arm amputation is associated with decreased heat pain thresholds in the face.

BACKGROUND: The mechanisms underlying chronic phantom limb pain (PLP) are complex and insufficiently understood. Altered sensory thresholds are often associated with chronic pain but quantitative sensory testing (QST) in PLP has so far been inconclusive due to large methodological variation between studies and small sample sizes. METHODS: In this study, we applied QST in 37 unilateral upper-limb amputees (23 with and 14 without PLP) and 19 healthy controls. We assessed heat pain (HPT), pressure pain, warmth detection and two-point discrimination thresholds at the residual limb, a homologous point and the thenar of the intact limb as well as both corners of the mouth. RESULTS: We did not find significant differences in any of the thresholds between the groups. However, PLP intensity was negatively associated with HPT at all measured body sites except for the residual limb, indicating lower pain thresholds with higher PLP levels. Correlations between HPT and PLP were strongest in the contralateral face (r = -0.65, p < 0.001). Facial HPT were specifically associated with PLP, independent of residual limb pain (RLP) and various other covariates. HPT at the residual limb, however, were significantly associated with RLP, but not with PLP. CONCLUSION: We conclude that the association between PLP and, especially facial, HPT could be related to central mechanisms. SIGNIFICANCE: Phantom limb pain (PLP) is still poorly understood. We show that PLP intensity is associated with lower heat pain thresholds, especially in the face. This finding could be related to central nervous changes in PLP.

Individualized Augmented Reality Training Reduces Phantom Pain and Cortical Reorganization in Amputees: A Proof of Concept Study.

Phantom limb pain (PLP) may be relieved using a visual representation of an intact limb. However, patients with distorted (telescoped) phantoms seem unable to associate with visualizations of intact limbs. A virtual arm visualization was matched to the individual's phantom perception and controlled in an augmented reality (AR) intervention. Seven PLP participants with telescoped phantoms performed 8 supervised home-based AR-training sessions (45 minutes each) within 2 weeks. The virtual arm was superimposed in AR onto their residual limb and controlled using electromyography from the residual limb. AR-training sessions included 3 AR tasks aimed at reengaging the neural circuits related to the lost limb. Agency (Rubber hand illusion questionnaire) and telescoping (proprioceptive drift and felt telescoping) were monitored after individual training sessions. fMRI during lip pursing was assessed before and after intervention. Pain rating index scores were reduced by 52% (mean change = -1.884, P = .032, d = 1.135). Numerical rating scale scores of PLP severity (0-6) in patients benefitting from the intervention were reduced by 41% (mean change = .93 P = .022, d = 1.334). The lip pursing task illustrated decreased cortical activity in the primary somatosensory cortex, which correlated to the reduced numerical rating scale scores of PLP severity. PERSPECTIVE: Two weeks of novel AR interventions in patients with telescoped phantoms demonstrated reduced PLP and reversal of cortical reorganization. This research highlights the potential of individualized AR interventions for PLP and indicate the importance of agency in this type of treatments.

Peripheral input and phantom limb pain: A somatosensory event-related potential study.

BACKGROUND: Following amputation, nearly all amputees report nonpainful phantom phenomena and many of them suffer from chronic phantom limb pain (PLP) and residual limb pain (RLP). The aetiology of PLP remains elusive and there is an ongoing debate on the role of peripheral and central mechanisms. Few studies have examined the entire somatosensory pathway from the truncated nerves to the cortex in amputees with PLP compared to those without PLP. The relationship among afferent input, somatosensory responses and the change in PLP remains unclear. METHODS: Transcutaneous electrical nerve stimulation was applied on the truncated median nerve, the skin of the residual limb and the contralateral homologous nerve in 22 traumatic upper-limb amputees (12 with and 10 without PLP). Using somatosensory event-related potentials, the ascending volley was monitored from the brachial plexus, the spinal cord, the brainstem and the thalamus to the primary somatosensory cortex. RESULTS: Peripheral input could evoke PLP in amputees with chronic PLP (7/12), but not in amputees without a history of PLP (0/10). The amplitudes of the somatosensory components were comparable between amputees with and without PLP. In addition, evoked potentials from the periphery through the spinal, subcortical and cortical segments were not significantly associated with PLP. CONCLUSIONS: Peripheral input can modulate PLP but seems insufficient to cause PLP. These findings suggest the multifactorial complexity of PLP and different mechanisms for PLP and RLP. SIGNIFICANCE: Peripheral afferent input plays a role in PLP and has been assumed to be sufficient to generate PLP. In this study we found no significant differences in the electrical potentials generated by peripheral stimulation from the truncated nerve and the skin of the residual limb in amputees with and without PLP. Peripheral input could enhance existing PLP but could not cause it. These findings indicate the multifactorial complexity of PLP and an important role of central processes in PLP.

Assessment of cortical reorganization and preserved function in phantom limb pain: a methodological perspective.

Phantom limb pain (PLP) has been associated with reorganization in primary somatosensory cortex (S1) and preserved S1 function. Here we examined if methodological differences in the assessment of cortical representations might explain these findings. We used functional magnetic resonance imaging during a virtual reality movement task, analogous to the classical mirror box task, in twenty amputees with and without PLP and twenty matched healthy controls. We assessed the relationship between task-related activation maxima and PLP intensity in S1 and motor cortex (M1) in individually-defined or group-conjoint regions of interest (ROI) (overlap of task-related activation between the groups). We also measured cortical distances between both locations and correlated them with PLP intensity. Amputees compared to controls showed significantly increased activation in M1, S1 and S1M1 unrelated to PLP. Neural activity in M1 was positively related to PLP intensity in amputees with PLP when a group-conjoint ROI was chosen. The location of activation maxima differed between groups in S1 and M1. Cortical distance measures were unrelated to PLP. These findings suggest that sensory and motor maps differentially relate to PLP and that methodological differences might explain discrepant findings in the literature.

ADRA2B genotype differentially modulates stress-induced neural activity in the amygdala and hippocampus during emotional memory retrieval.

RATIONALE: Noradrenaline interacts with stress hormones in the amygdala and hippocampus to enhance emotional memory consolidation, but the noradrenergic-glucocorticoid interaction at retrieval, where stress impairs memory, is less understood. OBJECTIVES: We used a genetic neuroimaging approach to investigate whether a genetic variation of the noradrenergic system impacts stress-induced neural activity in amygdala and hippocampus during recognition of emotional memory. METHODS: This study is based on genotype-dependent reanalysis of data from our previous publication (Li et al. Brain Imaging Behav 2014). Twenty-two healthy male volunteers were genotyped for the ADRA2B gene encoding the α2B-adrenergic receptor. Ten deletion carriers and 12 noncarriers performed an emotional face recognition task, while their brain activity was measured with fMRI. During encoding, 50 fearful and 50 neutral faces were presented. One hour later, they underwent either an acute stress (Trier Social Stress Test) or a control procedure which was followed immediately by the retrieval session, where participants had to discriminate between 100 old and 50 new faces. RESULTS: A genotype-dependent modulation of neural activity at retrieval was found in the bilateral amygdala and right hippocampus. Deletion carriers showed decreased neural activity in the amygdala when recognizing emotional faces in control condition and increased amygdala activity under stress. Noncarriers showed no differences in emotional modulated amygdala activation under stress or control. Instead, stress-induced increases during recognition of emotional faces were present in the right hippocampus. CONCLUSION: The genotype-dependent effects of acute stress on neural activity in amygdala and hippocampus provide evidence for noradrenergic-glucocorticoid interaction in emotional memory retrieval.

Do mirror glasses have the same effect on brain activity as a mirror box? Evidence from a functional magnetic resonance imaging study with healthy subjects.

Since its original proposal, mirror therapy has been established as a successful neurorehabilitative intervention in several neurological disorders to recover motor function or to relieve pain. Mirror therapy seems to operate by reactivating the contralesional representation of the non-mirrored limb in primary motor- and somatosensory cortex. However, mirror boxes have some limitations which prompted the use of additional mirror visual feedback devices. The present study evaluated the utility of mirror glasses compared to a mirror box. We also tested the hypothesis that increased interhemispheric communication between the motor hand areas is the mechanism by which mirror visual feedback recruits the representation of the non-mirrored limb. Therefore, mirror illusion capacity and brain activations were measured in a within-subject design during both mirror visual feedback conditions in counterbalanced order with 20 healthy subjects inside a magnetic resonance imaging scanner. Furthermore, we analyzed task-dependent functional connectivity between motor hand representations using psychophysiological interaction analysis during both mirror tasks. Neither the subjective quality of mirror illusions nor the patterns of functional brain activation differed between the mirror tasks. The sensorimotor representation of the non-mirrored hand was recruited in both mirror tasks. However, a significant increase in interhemispheric connectivity between the hand areas was only observed in the mirror glasses condition, suggesting different mechanisms for the recruitment of the representation of the non-mirrored hand in the two mirror tasks. We conclude that the mirror glasses might be a promising alternative to the mirror box, as they induce similar patterns of brain activation. Moreover, the mirror glasses can be easy applied in therapy and research. We want to emphasize that the neuronal mechanisms for the recruitment of the affected limb representation might differ depending on conceptual differences between MVF devices. However, our findings need to be validated within specific patient groups.

Effects of acute psychosocial stress on neural activity to emotional and neutral faces in a face recognition memory paradigm.

Previous studies have shown that acute psychosocial stress impairs recognition of declarative memory and that emotional material is especially sensitive to this effect. Animal studies suggest a central role of the amygdala which modulates memory processes in hippocampus, prefrontal cortex and other brain areas. We used functional magnetic resonance imaging (fMRI) to investigate neural correlates of stress-induced modulation of emotional recognition memory in humans. Twenty-seven healthy, right-handed, non-smoker male volunteers performed an emotional face recognition task. During encoding, participants were presented with 50 fearful and 50 neutral faces. One hour later, they underwent either a stress (Trier Social Stress Test) or a control procedure outside the scanner which was followed immediately by the recognition session inside the scanner, where participants had to discriminate between 100 old and 50 new faces. Stress increased salivary cortisol, blood pressure and pulse, and decreased the mood of participants but did not impact recognition memory. BOLD data during recognition revealed a stress condition by emotion interaction in the left inferior frontal gyrus and right hippocampus which was due to a stress-induced increase of neural activity to fearful and a decrease to neutral faces. Functional connectivity analyses revealed a stress-induced increase in coupling between the right amygdala and the right fusiform gyrus, when processing fearful as compared to neutral faces. Our results provide evidence that acute psychosocial stress affects medial temporal and frontal brain areas differentially for neutral and emotional items, with a stress-induced privileged processing of emotional stimuli.