Ulrike Lueken

• Prof. Dr. rer nat. habil.
• Professor (Full) at Humboldt-Universität zu Berlin

Introduction Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, brain age research in psychiatry has primarily examined mood and psychotic disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group. Methods 3D brain structural MRI scans fr...

Background Separation anxiety disorder (SEPAD) is characterized by pronounced fear or anxiety concerning separation from attachment figures. Despite its high lifetime prevalence, adult SEPAD often remains undetected due to a lack of diagnostic tools in multiple languages. The Adult Separation Anxiety Questionnaire (ASA-27) is a key instrument for a...

Introduction Cognitive–behavioural therapy (CBT) works—but not equally well for all patients. Less than 50% of patients with internalising disorders achieve clinically meaningful improvement, with negative consequences for patients and healthcare systems. The research unit (RU) 5187 seeks to improve this situation by an in-depth investigation of th...

Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of ‘exposure.’ Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and...

Background: Chat-based counseling services are popular for the low-threshold provision of mental health support to youth. In addition, they are particularly suitable for the utilization of natural language processing (NLP) for improved provision of care. Objective: Consequently, this paper evaluates the feasibility of such a use case, namely, the N...

Background: Although meta-analyses suggest comparable efficacy of cognitive-behavioral therapy (CBT) in older adults compared to working-age adults, little is known about its effectiveness in naturalistic settings across different age groups. Hence, this study compared symptom change, attrition rates, and treatment duration in outpatient CBT betwee...

Background The Personalized Advantage Index (PAI) shows promise as a method for identifying the most effective treatment for individual patients. Previous studies have demonstrated its utility in retrospective evaluations across various settings. In this study, we explored the effect of different methodological choices in predictive modelling under...

Background: The COVID-19 pandemic exposed a substantial portion of society to multiple stressors, while access to mental health care was limited. To address this, we introduced a digital stepped-care program rooted in cognitive–behavioral therapy (CBT) principles, aiming to alleviate mental health distress among the general public seeking help. Met...

Introduction While cognitive-behavioural therapy (CBT) for obsessive-compulsive disorder (OCD) and anxiety disorders (ADs) has been proven to be effective and is commonly recommended, a considerable proportion of patients remain symptomatic, do not respond to treatment or discontinue it. Thus, augmentation strategies aimed at enhancing CBT outcomes...

Childhood adversity is a strong predictor for developing psychopathological conditions. Exposure to threat-related childhood adversity has been suggested to be specifically linked to altered emotional learning as well as changes in neural circuits involved in emotional responding and fear. Learning mechanisms are particularly interesting as they ar...

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in funct...

The functional neuropeptide S receptor 1 (NPSR1) gene A/T variant (rs324981) is associated with fear processing. We investigated the impact of NPSR1 genotype on fear processing and on symptom reduction following treatment in individuals with spider phobia. A replication approach was applied [discovery sample: Münster (MS) nMS = 104; replication sam...

Objective: Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) s...

BACKGROUND Chat-based counseling services are popular for the low-threshold provision of mental health support to the youth. Also, they are particularly suitable for the utilization of Natural Language Processing (NLP) for an improved provision of care. OBJECTIVE Consequently, this paper evaluates the feasibility of such a use case, namely the NLP...

Objective: Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII)...

Chat-based counseling hotlines emerged as a promising low-threshold intervention for youth mental health. However, despite the resulting availability of large text corpora, little work has investigated Natural Language Processing (NLP) applications within this setting. Therefore, this preregistered approach (OSF: XA4PN) utilizes a sample of approxi...

ZUSAMMENFASSUNG Die Neuordnung der Angst- oder furchtbezogenen Störungen in der ICD-11 wird, auch im Vergleich zum DSM-5, beschrieben. Wichtigste Veränderungen sind die gleichberechtigt nebeneinanderstehenden Kategorien „Panikstörung“ und „Agoraphobie“, die Einordnung von „Trennungsangststörung“ und „Selektiver Mutismus“ in das Kapitel sowie die Au...

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to i...

The COVID-19 pandemic and associated countermeasures had an immensely disruptive impact on people’s lives. Due to the lack of systematic pre-pandemic data, however, it is still unclear how individuals’ psychological health has been affected across this incisive event. In this study, we analyze longitudinal data from two healthy samples (N = 307) to...

Natural Language Processing (NLP) is a promising approach for the extraction of meaningful information from text data in clinical psychology. While ample resources cover the implementation of such techniques, the majority of them focus on English. In contrast, this tutorial paper provides a hands-on Python guide for applying NLP on an exemplary Ger...

Exposure to adverse childhood experiences (ACEs) is a strong predictor for developing behavioral, somatic and psychopathological conditions. Exposure to threat-related early adversity has been suggested to be specifically linked to altered emotional learning as well as changes in neural circuits involved in emotional responding and fear. Learning m...

Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of ‘exposure.’ Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and...

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. The extent to which these signatures are shared across different phenotypes remains unclear, as well-powered transdiagnostic comparisons are still largely missing. We used resting-state functional magnetic resonance imaging (rsfMRI) to investiga...

The COVID-19 pandemic and associated countermeasures had an immensely disruptive impact on people’s lives. Due to the lack of systematic pre-pandemic data, however, it is still unclear how individuals’ psychosocial health has been affected across this incisive event. In this study, we analyze longitudinal data from two healthy samples ( N = 307) to...

Chat-based counseling hotlines emerged as a promising low-threshold intervention for youth mental health. However, despite the resulting availability of large text corpora, little work has investigated Natural Language Processing (NLP) applications within this setting. Therefore, this preregistered approach (OSF: XA4PN) utilizes a sample of approxi...

Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of exposure. Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and c...

Machine-learning prediction studies have shown potential to inform treatment stratification, but recent efforts to predict psychotherapy outcomes with clinical routine data have only resulted in moderate prediction accuracies. Neuroimaging data showed promise to predict treatment outcome, but previous prediction attempts have been exploratory and r...

Introduction: Personalization is a much-discussed approach to improve adherence and outcomes for Digital Mental Health interventions (DMHIs). Yet, major questions remain open, such as (1) what personalization is, (2) how prevalent it is in practice, and (3) what benefits it truly has. Methods: We address this gap by performing a systematic literat...

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a gl...

Background: The COVID-19 pandemic and accompanying restrictions are associated with substantial psychological distress. However, it is unclear how this increased strain translates into help-seeking behavior. Here, we aim to characterize those individuals who seek help for COVID-19 related psychological distress, and examine which factors are associ...

The COVID-19 pandemic and related containment measures are affecting mental health, especially among patients with pre-existing mental disorders. The aim of this study was to investigate the effect of the first wave and its aftermath of the pandemic in Germany (March–July) on psychopathology of patients diagnosed with panic disorder, social anxiety...

Adverse experiences interact with individual vulnerability in the etiology of mental disorders, but due to the paucity of longitudinal studies, their precise interplay remains unclear. Here, we investigated how individual differences in threat responsiveness modulated adjustments in negative affect during the COVID-19 pandemic. Participants (N = 44...

Despite striking empirical support, exposure-based treatments for anxiety disorders are un-derutilized. This is partially due to clinicians’ concerns that patients may reject exposure or experience severe side effects, particularly in intensive forms of exposure. We examined ac-ceptance and side effects of two randomly assigned variants of predicti...

Despite striking empirical support, exposure-based treatments for anxiety disorders are underutilized. This is partially due to clinicians’ concerns that patients may reject exposure or experience severe side effects, particularly in intensive forms of exposure. We examined acceptance and side effects of two randomly assigned variants of prediction...

Individual responses to behavioral treatment of anxiety disorders vary considerably, which requires a better understanding of underlying processes. In this study, we examined the violation and change of threat beliefs during exposure. From 8,484 standardized exposure records of 605 patients with different anxiety disorders, learning indicators were...

It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertaint...

Angst ist eine überlebenswichtige Emotion. Im Folgenden geben wir einen Überblick über basale Defensivmechanismen und furchtbezogene Lernprozesse und zeigen, wie ein biologisch-evolutionäres Verständnis gesunder und pathologischer defensiver Reaktivität Betroffenen helfen kann, Angstsymptome zu begreifen und ein expositionsbasiertes Behandlungsrati...

It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertaint...

The COVID-19 pandemic and related containment measures are affecting mental health, especially among patients with pre-existing mental disorders. The aim of this study was to investigate the effect of the first wave and its aftermath of the pandemic in Germany (March–July) on psychopathology of patients diagnosed with panic disorder, social anxiety...

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 ( RBFOX1 ) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating...

Background The COVID-19 pandemic and accompanying restrictions are associated with substantial psychological distress. However, it is unclear how this increased strain translates into help-seeking behavior. Here, we aim to characterize those individuals who seek help for COVID-19 related psychological distress, and examine which factors are associa...

Individual responses to behavioral treatment of anxiety disorders vary considerably, calling for better understanding of underlying processes. This study examined the violation and change of threat beliefs during exposure. From 8484 standardized exposure records of 605 patients with different anxiety disorders, learning indicators were derived: Exp...

rsFC fMRI Seed-based analysis of distinct pattern of anxiety diagnoses.

This is a Poster on a Pre-post evaluation of a psychological help program during the COVID-19 pandemic to reduce depressive, anxiety and somatic symptoms.

Background Models of anxiety disorders and the rationale of exposure therapy (ET) are grounded on classical fear conditioning. Yet, it is unclear whether lower fear ratings of conditioned safety versus threat cues and corresponding neural markers of safety-learning and/or fear inhibition assessed before treatment would predict better outcomes of be...

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging meth...

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through th...

The COVID-19 pandemic is one of the most serious health and economic crises of the 21st century. From a psychological point of view, the COVID-19 pandemic and its consequences can be conceptualized as a multidimensional and potentially toxic stressor for mental health in the general population. This selective literature review provides an overview...

Recent studies indicate differential involvement of the centromedial amygdala (CM) and the bed nucleus of the stria terminalis (BNST) during processing (anticipation and confrontation) of threat stimuli. Here, temporal predictability was shown to be a relevant factor. In this study, we want to investigate the relevance of these effects, which were...

Introduction Many adults, adolescents and children are suffering from persistent stress symptoms in the face of the COVID-19 pandemic. This study aims to characterize long-term trajectories of mental health and to reduce the transition to manifest mental disorders by means of a stepped care program for indicated prevention. Methods and analysis Us...

Background: The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions. Methods: This multicenter randomized controlled trial compared two variant...

Background Patients with specific phobia (SP) show altered brain activation when confronted with phobia-specific stimuli. It is unclear whether this pathogenic activation pattern generalizes to other emotional stimuli. This study addresses this question by employing a well-powered sample while implementing an established paradigm using nonspecific...

While being highly effective on average, exposure-based treatments are not equally effective in all patients. The a priori identification of patients with a poor prognosis may enable the application of more personalized psychotherapeutic interventions. We aimed at identifying sociodemographic and clinical pre-treatment predictors for treatment resp...

Background As overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pre-treatment levels of fear generalization in spider-phobic patients are related to their response to exposure-based treatment, in order to identify pre-treatment moderators of treatment success. Methods Ninety patients with spider phobia...

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unc...

As overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pre-treatment levels of fear generalization in spider-phobic patients are associated with their response to exposure-based treatment, in order to identify pre-treatment correlates of treatment success. Ninety patients with spider phobia completed pre-...

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD pati...

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety...

Abstract This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci as...

Zusammenfassung. Die COVID-19-Pandemie als multidimensionaler und potenziell toxischer Stressfaktor führt auch in Deutschland zu psychischen Problemen in der Allgemeinbevölkerung und wird voraussichtlich einen Anstieg der Inzidenz- und Prävalenzraten psychischer Störungen bedingen. In diesem Positionspapier erfolgt daher eine wissenschaftlich diffe...

Objectives: Machine learning models predicting treatment outcomes for individual patients may yield high clinical utility. However, few studies tested the utility of easy to acquire and low-cost sociodemographic and clinical data. In previous work, we reported significant predictions still insufficient for immediate clinical use in a sample with br...

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unc...

Although cognitive behavioral therapy (CBT) is an established and efficient treatment for a variety of common mental disorders, a considerable number of patients do not respond to treatment or relapse after successful CBT. Recent findings and approaches from neuroscience could pave the way for clinical developments to enhance the outcome of CBT. He...

Background: By understanding specific differences between responders to a treatment and non-responders, treatment modalities may be fitted to the individual in order to increase effectiveness, a concept known as “precision medicine”. This systematic review and meta-analysis investigated which pretreatment patient and family characteristics may pred...

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. One-hundred forty-thr...

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging meth...

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA‐Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega‐analysis of a large number of brain structural scans. In this process, the group was confronted with many methodolo...

Following the interoceptive inference framework, we set out to replicate our previously reported association of self-control and interoceptive prediction and strived to investigate the neural underpinnings subserving the relationship between self-control and aversive interoceptive predictive models. To this end, we used fMRI and a within-subject de...

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodolo...

Während in der somatischen Medizin mittlerweile eine Vielzahl von biologischen Markern für die Diagnostik und Therapieplanung vorliegen, gibt es keine vergleichbaren bio­logischen oder psychologischen Marker für psychische Störungen. Hier sind die Pathogenese und Wirkung psychotherapeutischer Interventionen durch eine Vielzahl mitei­nander interagi...

Objectives: Temperamental traits as ascertained by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto-Questionnaire (TEMPS-A) have been suggested as promising intermediate phenotypes of mental disorders. In anxiety disorders, however, TEMPS scales and their genetic underpinnings are still understudied. Methods: TEMPS-A scores in...

Objective: Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder. Methods...

The availability of large-scale datasets and sophisticated machine learning tools enables developing models that predict treatment outcomes for individual patients. However, few studies used routinely available sociodemographic and clinical data for this task, and many previous investigations used highly selected samples. This study aimed to invest...

d-cycloserine (DCS), a partial NMDA-receptor agonist, seems to be a promising enhancer for exposure therapy in anxiety disorders. It has been tested successfully in animal models of fear extinction, where DCS enhanced extinction learning. Applied in clinical studies, results of DCS-augmented exposure therapy remain ambiguous, calling for a deeper u...

Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neur...