European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 https://doi.org/10.1007/s00406-020-01159-2 ORIGINAL PAPER Longitudinal determination of resilience in humans to identify mechanisms of resilience to modern‑life stressors: the longitudinal resilience assessment (LORA) study A. Chmitorz1,2 · R. J. Neumann3 · B. Kollmann1,4  · K. F. Ahrens3 · S. Öhlschläger3 · N. Goldbach3 · D. Weichert1 · A. Schick4,5,6 · B. Lutz4,7 · M. M. Plichta3 · C. J. Fiebach8,9 · M. Wessa4,10 · R. Kalisch4,5 · O. Tüscher1,4 · K. Lieb1,4 · A. Reif3 Received: 5 February 2020 / Accepted: 29 June 2020 / Published online: 18 July 2020 © The Author(s) 2020 Abstract Resilience is the maintenance and/or quick recovery of mental health during and after periods of adversity. It is conceptual- ized to result from a dynamic process of successful adaptation to stressors. Up to now, a large number of resilience factors have been proposed, but the mechanisms underlying resilience are not yet understood. To shed light on the complex and time-varying processes of resilience that lead to a positive long-term outcome in the face of adversity, the Longitudinal Resilience Assessment (LORA) study has been established. In this study, 1191 healthy participants are followed up at 3- and 18-month intervals over a course of 4.5 years at two study centers in Germany. Baseline and 18-month visits entail multimodal phenotyping, including the assessment of mental health status, sociodemographic and lifestyle variables, resilience factors, life history, neuropsychological assessments (of proposed resilience mechanisms), and biomaterials (blood for genetic and epigenetic, stool for microbiome, and hair for cortisol analysis). At 3-monthly online assessments, subjects are monitored for subsequent exposure to stressors as well as mental health measures, which allows for a quantitative assessment of stressor- dependent changes in mental health as the main outcome. Descriptive analyses of mental health, number of stressors including major life events, daily hassles, perceived stress, and the ability to recover from stress are here presented for the baseline sample. The LORA study is unique in its design and will pave the way for a better understanding of resilience mechanisms in humans and for further development of interventions to successfully prevent stress-related disorder. Keywords Longitudinal · Resilience · Modern-life stressors · Deep phenotyping Introduction extent be traced back to the influence of exogenous or endog- enous stressors (e.g., traumatizing events, challenging life Recent data from epidemiological surveys in the European circumstances or life transitions, or physical illness) [1]. The Union show that each year, approximately 30% of the popu- high incidence of stress-related disorders, the considerable lation suffer from a mental disorder, such as anxiety, depres- individual burden, as well as socioeconomic costs associ- sion, chronic pain, or addiction, that can at least to some ated with them make the promotion of mental health one of the great challenges industrialized countries currently have to face. Progress in our understanding of disease mecha- A. Chmitorz, R. J. Neumann, K. Lieb, A. Reif and B. Kollmann nisms and in the development of new therapies in the last authors are contributed equally. decades has been limited despite intense research. The inci- K. Lieb and A. Reif authors are contributed equally. dence of stress-related mental disorders remains high. It may be, therefore, essential to complement pathophysiological Electronic supplementary material The online version of this research with an alternative strategy, which is to investi- article (https ://doi.org/10.1007/s00406 -020-01159 -2) contains supplementary material, which is available to authorized users. gate protective mechanisms that support the maintenance of mental health during and after adversity (e.g., poten- * B. Kollmann tially traumatizing events, challenging life circumstances, bianca.kollmann@lir-mainz.de and physical illness). Focusing on resilience rather than on Extended author information available on the last page of the article pathophysiology represents a paradigm shift in mental health Vol.:(012 3456789) 1036 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 research and has great potential for the development of new outcome and are difficult to replicate [9]. Moreover, it has prevention strategies [2]. been noted that many of these resilience factors overlap Psychological resilience refers to the observation that conceptually and presumably mediate, correlate with, or many individuals do not or only temporarily become ill, depend on each other [2, 15]. For instance, emotion regu- despite exposure to significant psychological or physical lation, coping, or problem solving are similar concepts and adversity [3–5]. In this regard, adversity refers to stressors more distal factors such as social support, life history, or of modern life including ‘macrostressors’ (i.e., potentially genotype may affect resilience by shaping the way an indi- traumatizing events, such as man-made or natural disasters) vidual regulates his/her emotions or copes with stressors as well as ‘microstressors’ or so-called ‘daily hassles’ (i.e., [2]. This calls for the identification and understanding of irritating, frustrating, and distressing demands that to some mediating mechanisms (‘resilience mechanisms’), i.e., a extent are part of every-day interactions with the environ- presumably smaller number of shared cognitive, physi- ment) [6]. Focusing on mechanisms of resilience, rather than ological and/or neural pathways, that provide protection disease, may be a promising approach to promote the pre- against stress-related impairments. vention of stress-related mental dysfunctions. Resilience has To identify and investigate such resilience mechanisms, previously been considered to be a stable personality trait the Collaborative Research Center (CRC) 1193 ‘Neurobiol- [7, 8]. However, nowadays, most theorists define resilience ogy of resilience to stress-related mental dysfunction: from as an outcome, i.e., the absence of mental or related somatic understanding mechanisms to promoting prevention’, funded diseases after a potentially traumatizing event, or after a pro- by the German Research Foundation (DFG), was established longed period of stress [5, 9, 10]. at the Universities of Mainz and Frankfurt and the Leibniz One consequence of this conceptualization of resilience Institute for Resilience Research (LIR; formerly German as an outcome is that resilience cannot be measured before Resilience Center) in Mainz. The CRC assesses resilience an individual has encountered stressors, for example, by and its underlying mechanisms at several levels of analysis, cross-sectionally using a personality questionnaire. We integrating human studies and animal models in a transla- recently suggested a conceptual framework for the study of tional manner. Central to the CRC 1193 is a large longi- resilience and made proposals for outcome variables (com- tudinal human cohort study, the Longitudinal Resilience pare [2]). In the simplest possible scenario, we suggested to Assessment (LORA) study. This paper aims at providing an relate the change in mental health problems (P), measured overview of the research program, the methods used, and to at two time points ( TA and T B), to the individual cumulative present baseline data of the LORA study cohort of enrolled stressor load (i.e., the sum or amount of stressors) experi- healthy subjects. enced between TA and T B. In doing so, one can calculate a parametric score that expresses how an individual’s mental health reacts to stressor exposure. It is assumed that a person Research program is more resilient at T B if that person has developed less men- tal problems between TA and TB than expected in proportion LORA is currently conducted at the University Medical to the accumulated stressor load. As a consequence, indi- Center Mainz in cooperation with the LIR and the University viduals with high cumulative stressor load and low mental Hospital of the Goethe University Frankfurt. It comprises a health problems at a given time point are considered to be human cohort N = 1.191 (Frankfurt: n = 611; Mainz: n = 580) more resilient than, for instance, individuals experiencing an that has been deep-phenotyped at study entry and is cur- equal stressor load and more mental health problems in that rently followed up for a minimum of 3 years in 18-month same time period. Necessarily, to operationalize resilience intervals. Between baseline assessments, participants are as an outcome in this or comparable ways, prospective, lon- monitored every 3 months for mental health as well as gitudinal study designs are required [9, 11]. encountered stressors in interim online stressor monitoring Current resilience research is still mainly phenomeno- during the entire study period. logical, often restricted to measuring the so-called ‘resil- The two main research aims of the LORA study are: ience factors’, that are statistically related to the outcome of resilience. Consequently, published reviews enumer- • Aim 1 To characterize participants for their resilience ate long lists of resilience factors, which include external to modern-life stressors over time and to operational- factors, such as socioeconomic status or social support, ize resilience in a quantitative–parametric fashion (i.e., internal factors, such as certain beliefs (e.g., self-efficacy) dimensionally rather than categorically). or skills (e.g., emotion regulation, problem solving), or • Aim 2 To identify and understand potential underlying more recently also neurobiological, (epi)genetic, hormo- mediating mechanisms of resilience to modern every-day nal, immunological, or other molecular factors [12–15]. life stressors. Frequently, these factors explain only little variance in the 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1037 Furthermore, LORA has a third aim within the CRC 1193 ing emotion regulation, cognitive flexibility, emotional consortium, namely to provide human subprojects within the interference inhibition, fear conditioning and extinction, CRC 1193 with deeply phenotyped subjects, systematically and appraisal styles. Furthermore, repeated quantita- characterized for their longitudinal resilience outcome, for tive assessments of encountered modern-life stressors, the purpose of experimentally investigating hypothesized including critical life events and daily hassles, as well as resilience mechanisms in these subjects using, among others, stressor-dependent changes in mental health (via interim neuroimaging and neurobiological methods. online stressor monitoring) and biosamples (hair cortisol and microbiome), are assessed every 3 months to investi- Tasks gate resilience outcomes over time (see Fig. 1). Changes between the baseline assessments, together with informa- The main tasks to achieve the aforementioned aims are: tion from the interim online assessments, will aid in oper- ationalizing resilience in a dimensional fashion, including 1. In-depth phenotyping of N = 1.200 subjects at baseline possible trajectories of resilience outcomes. assessments in 18-month intervals, including psychologi- 2. Using these data, potential underlying neuropsychological cal, sociodemographic, environmental, lifestyle, genetic resilience mechanisms and/or biomarkers [such as (epi-) and epigenetic resilience factors, experienced stress in the genetic markers and microbiome] shall be identified. months prior to the baseline measurement using hair cor- Also, these assessments will aid in the identification and tisol samples, and microbiome analyses taken from stool understanding of potential underlying mediating mecha- samples in a community sample from the German Rhine- nisms of resilience to modern every-day life stressors. Main region. Also, a neuropsychological test battery is 3. Subprojects of the CRC 1193 that conduct experimental conducted at baseline and every 18 months, investigat- studies with humans will be provided with subjects that Fig. 1 LORA study design and assessment categories 1 3 1038 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 have been systematically characterized for their longi- the university medical centers, libraries, shops, and gyms) tudinal resilience outcome. For this purpose, there are and a webpage setup specifically for the project (https :// also cooperations with external projects. So far, these lora-studie .de/). Potential participants contacted the study include: (1) EU H2020 funded project “Eat2BeNICE”; centers via phone or e-mail. within the scope of this project, further analyses of the Interested participants were then re-contacted by trained microbiome (via 16S rRNA sequencing) are funded. (2) student assistants via phone or letter and provided with By means of collaboration with the Psychiatric Genomic study information. They were screened for study eligibility Consortium (PGC), we could secure funds for genome- by trained staff using structured in-house developed tel- wide genotyping using the PsychChip. (3) A BEDRE- ephone interviews. Inclusion criteria were: age 18–50 years HELSE project on the epigenetic signature of ADHD (the upper age limit is set to minimize potential impacts of allows to perform epigenome-wide analysis of part of organic brain disorders), normal or corrected vision, suf- the sample using the EPIC array; (4) EU H2020 funded ficient mastery of the German language, and the ability to project “DynaMORE” uses amongst others LORA data provide informed consent. Sufficient knowledge of Ger- to develop an in silico model of stress resilience; (5) man can be inferred from the telephone screening, which the State of Rhineland-Palatinate funded the Gutenberg takes about 15 min. Also, participants are asked during that Brain Study (GBS), which is a platform project of the screening, whether German is their mother tongue. How- LIR. The GBS has established a population-based sam- ever, being a non-native German speaker does not lead to ple of 4500 subjects from Mainz. Further collaborations study exclusion, as long as the language proficiency is suffi- are actively sought for, to leverage the information that cient to understand the content of the phone call. Exclusion is gathered in LORA and interested parties are asked to criteria were: lifetime diagnosis of schizophrenia or bipolar approach the LORA PIs to this end. disorder, organic mental disorders, substance dependence syndromes other than nicotine, as well as any other cur- rent severe axis I disorder or current severe medical condi- Description of the LORA study design tions. Participants with known learning disabilities, serious neurological disorders (e.g., tumors in the central nervous The LORA study is a population-based, prospective, lon- system), or participants who had taken part in a drug trial gitudinal, multi-center cohort study including adults up to in the previous 6 months were also excluded. 50 years at study entry. Data collection for the first base- Participants who met the screening criteria were invited line assessment started on February 1st 2017 and continued for an initial briefing session and gave written informed con- until July 15th 2019. Planned longitudinal assessment will sent. Furthermore, participants were assessed diagnostically be ongoing for at least 3 years. on the International Neuropsychiatric Interview (M.I.N.I [16, The study includes baseline assessments at the study centers: 17]) to rule out the existence of any current mental disorders. at study entry (B0/T0), at 1.5 years (B1/T6) and 3 years (B2/ For n = 10 participants, this screening was positive and further T12), all participants are characterized in detail. Here, pheno- study participation was precluded (but referral to the outpa- typing includes questionnaires on sociodemographic, mental tient departments of the respective participating study site’s health, life history, psychological, and lifestyle-related variables psychiatric department for further diagnosis and treatment (including upstream resilience factors) (see Table 1a). Further- was offered). Figure 2 provides an overview of the recruit- more, biological parameters (blood, stool, and hair samples), ment process. If the diagnostic interview was negative, partici- anthropometric and current physical fitness components, as pants were eligible for study participation and enrolled for full well as a neuropsychological test battery are conducted. For study assessment. Additionally, participants who completed the latter, battery tasks can be considered as proxy measures less than 50% of the first baseline assessment (B0/T0) were of the putative neurobiological resilience mechanisms (see excluded from further study participation. For the on-site base- Table 1b). Between baseline assessments, every 3 months, addi- line assessments, participants are monetarily reimbursed with tional interim online stressor monitoring is conducted during 60€. Participation at the online stressor monitoring is rewarded the entire study period (see Fig. 1 for details on study design). with a token system, were subjects can gain up to three tokens The design allows for the assessment of healthy subjects of per monitoring and 12 tokens per year. Each token is worth 5€ a large age range and follows them up as they are exposed to and is exchanged against a monetary compensation. naturally occurring life stressors in a modern society. Procedures Sample recruitment According to the described study design, participants are Participants were recruited via online or printed adver- invited on site to the baseline assessments for detailed char- tisements, public advertisements (at the local universities, acterization at 18-month intervals. In between baseline 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1039 assessments, additional interim online stressor monitoring is of all participants, who agree to submit a sample. Informa- applied every 3 months (see also Fig. 1). The detailed study tion about (chemical) hair treatments (i.e., colouring, perms, design and applied assessment categories are described in or using a strengthening iron) prior to sample collection is detail below. gathered. For participants with hair shorter than 3 cm, no hair samples are collected, but these participants will remain Online database in the study. Since participants are asked to send in their hair samples by mail for the following five interim online stressor Besides on-site assessments at baseline and additional monitoring, they are also provided with packing material for interim online stressor assessments, participants fill out the following five measurement time points (T1-T5; 3, 6, 9, questionnaires in an online data base system (secuTrial© 12, and 15 months). Anthropometric measurements (weight, electronic data capture system, www.secutr ial.com), which height, hip, and waist circumferences) are conducted using a adheres to the Guidelines for Good Clinical Practice (GCP). calibrated electronic scale (Seca, Birmingham, UK) with an The database provides an application for online assessments, accuracy of 0.1 kg for weight and a stadiometer (Seca) with through which the questionnaires assessing sociodemo- an accuracy of 0.1 cm for height (participants were not wear- graphic, lifestyle, and psychological variables are collected ing shoes). Waist circumference is measured to the nearest at the initial baseline assessment (B0/T0) and subsequent 0.1 cm midway between the lowest rib and the top of the baseline assessments (B1/T6 and B2/T12), and the 3-month iliac crest. Hip circumference measurement is taken around interim online stressor monitoring. All surveyed data are the widest portion of the buttocks. Both measures are con- stored in the online data base system. ducted according to the WHO recommendations [76]. For the stool sample collection, the OMNIgene•Gut kits (DNA Genotek Inc. Ttawa, ON, Canada) are used. These consist of Baseline assessments a tube of stabilisation liquid and a ball bearing. Two tubes, as well as a user manual for the stool sample collection at Participants who fulfil the inclusion criteria are invited to B0/T0 and the first 3-month measurement time point (T1), the baseline assessments for detailed characterization at the are handed out to the participants. They are asked to place respective study centers. These are conducted on 2 days, stool faeces in the tube lid, which is designed to break up which are separated by no more than 7 days. the faeces, and return the first tube at day 2, within 7 days. B0/T0, day 1 (40–60 min) After an initial briefing session, The second tube from T1 is returned by mail 3 months later. written informed consent is obtained and participants are On arrival the samples are frozen immediately at − 80 °C. registered in the study database, where a random individual Finally, participants are introduced to the online assess- identification number is being generated. ment application of the database for questionnaire assess- Afterwards, the International Neuropsychiatric Interview ments and asked to complete the questionnaires within a (M.I.N.I.) [16] is used to rule out the existence of any cur- week. Questionnaires entail items assessing socio-demo- rent mental disorders. Provided that all inclusion criteria graphics, mental health, life history, psychological, and are met, the actual baseline assessment begins with the lifestyle-related variables. The estimated completion time conduction of the multifaceted empathy test (MET) [38]. is 160 min. A complete list of applied questionnaires is given Blood samples are taken from the non-fasting participants by in Table 1a. venous puncture (2 × EDTA tubes; approximately 18 ml) to B0/T0, day 2 (approx. 180 min) First, participants hand assess fluid biomarkers, including (epi-)genetic markers for in stool samples and take part in a drug screening. If the genotyping. Blood samples are subsequently stored at refrig- screening is negative, they are then asked to proceed. If erator temperature until DNA isolation. Also, hair samples screened positive, participants are excluded from the study. for cortisol determination are collected (see supplement for Then, participants are asked to fill out questionnaires meas- detailed information about biosample outcomes). For hair uring state-dependent variations in anxiety (i.e., State-Trait samples, two to three hair strains of at least 3-cm length are Anxiety Inventory; STAI-S [77, 78]) and the Positive and cut as close as possible to the scalp at the posterior vertex Negative Affect Schedule (PANAS; [50]). This is followed region [74]. Samples are wrapped in aluminium foil; the by a neuropsychological test battery, which assess the fol- scalp end was marked and stored in a dark, dry place at room lowing potential neuropsychological resilience mechanisms: temperature until the end of complete baseline assessment. (a) cognitive flexibility, (b) emotional interference inhibi- Given an average hair growth rate of 1 cm per month, earlier tion, (c) positivity bias, (d) volitional emotional regula- described by Wenning [75], the examination of 3-cm hair tion, and e) differential fear conditioning (discrimination) segment allows to assess cumulative hair cortisol concen- and extinction. Table 1b provides a description of the tasks tration over a period of 3 months, consistent with assessed and the measured potential underlying neuropsychological stressor load every 3 months. Hair samples are collected mechanisms. Subsequently, subjects are asked to participate 1 3 1040 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 Table 1 (a) Questionnaires and (b) neuropsychological tests used in the LORA study (a) Questionnaires Topic Questionnaire B F 3m #I Mental health General health questionnaire-28 (GHQ-28) [18, 19] x x x 28 Health questionnaire for patients (PHQ-D) [20, 21] x x 16 Mini international neuropsychiatric interview (M.I.N.I.) [16, 17] x x Micro- and macrostressors  History of critical life events Life events checklist from LHC (adapted from Canli et al. [22]) x x x 27  Daily hassles Mainz Inventory of Microstressors (MIMS) [23, 24] x x x 58  Childhood Trauma Childhood trauma questionnaire (CTQ) [26, 27] x x 25  Perceived stress Perceived stress scale (PSS) [28]; unpublished translation by A. Büss- x x x 10 ing, University of Witten/Herdecke  Maltreatment and abuse Maltreatment and abuse chronology of exposure (MACE) [29] x 18  Trauma Harvard trauma questionnaire (HTQ) [30] x 35 Psychological variables  Ability to bounce back Brief resilience scale (BRS) [31, 32] x x 6  Cognitive emotion regulation Cognitive emotion regulation questionnaire (CERQ) [33, 34] x x 29  Coping flexibility Coflex [35]; German version translated by study site x x 13  Coping style Brief Cope [36, 37] x x 28  Empathy Multifaceted empathy test (MET) (subsection: accuracy) [38] x x 40  Hardiness Hardiness Scale ([39]; translated by study site) x x 12  Impulsive behavior Urgency Premeditation Perseverance and Sensation Seeking Impulsive x x 45 Behavior Scale (UPPS) [40, 41]  Impulsivity Eight item impulsive behavior scale (I-8) [42] x x 8  Interpersonal reactivity Interpersonal reactivity index (IRI) [43] x x 28  Locus of control Locus of control scale [44, 45] x x 28  Optimism Life orientation test (LOT-R) [46, 47] x x 10  Perceived social support Social support questionnaire (F-SozU) [48] x x 14  Personality Big-five-inventory (BFI-10) [49] x x 10  Positive and negative affect Positive and negative affect schedule (PANAS) [50, 51] x x 20  Positive appraisal style gPASS (Kalisch et al. in prep.) x x 29  Resilience factors Connor–Davidson resilience scale (CD-Risk) [52, 53] x x 25  Self-efficacy General self-efficacy scale (GSE) [54] x x 10  Sense of coherence Orientation to life questionnaire [55, 56] x x 29  Social desirability Social desirability scale-gamma (KSE-G) [57] x x 6  State-Trait Anger State-trait anger anxiety questionnaire (STAXI) [58] x x 44  Well-being WHO questionnaire on well-being (WHO 5) [59, 60] x x 5  Identity Adapted from Skalen zur Messung der ethnischen Identität (MEIM) x 7 (GESIS [61])  Humiliation Humiliation scale (Lindert and Mollica, in prep.) 26 Sociodemographic variables  General sociodemographic data General questionnaire for sociodemographic data, family history, x x 56 ethnical background, employment/salary  Migration Migration status questionnaire (based on Nesterko and Glaesmer) [62]) x x 5 Lifestyle variables  Alcohol use disorder Alcohol use disorder identification test (AUDIT) [63] x x 10  Nicotine dependence Fagerstrom test for nicotine dependence [64] x x 6  Drug consumption General questionnaire about illegal drug consumption (questionnaire x x 6 created by study sites)  Physical activity International physical activity questionnaire (IPAQ) [65, 66] x x 27  Physical fitness International fitness scale (IFIS) [67] x x 5  General health variables General questions concerning health and lifestyle (based on: GESIS 12 [61]) 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1041 Table 1 (continued) Neuropsychological tests Resilience mechanism Task description Psychological flexibility For the assessment of switch costs, stability (distractor inhibi- tion cost), and dispositional flexibility (i.e., the spontaneous switching rate in the face of ambiguous cues); the stability/ flexibility task is used. Participants continuously perform a task on digits presented above a fixation cross (ongoing task, e.g., odd/even judgment on digits between 1 and 9). Infrequently, a second digit is presented beneath fixation, and depending on three different brightness conditions, partici- pants have to either switch to the lower digit and perform a different task when the lower digit is brighter (e.g., < / > 5 judgment; flexibility condition) or ignore the lower digit when it is darker than the upper digit (distractor inhibition; stability condition). In the third of three conditions, the brightness difference between the two digits is so subtle that it is not consciously detectable (ambiguous condition). Here, the spontaneous switching rate is examined as an indicator of dispositional cognitive flexibility; established by Armbruster et al. [68] Emotional interference inhibition A classical flanker task, assessing emotional response interfer- ence inhibition, during which participants need to respond to a target cue presented in the center of the screen, surrounded by distractor cues. Before each target cue presentation, par- ticipants see a picture from the International Affective Picture Set (IAPS) database for 500 ms, differing in emotional valence (i.e., aversive or neutral). Then, a row of seven arrows is presented, which either all point congruently to the left/ right side or the target cue points to the opposite site com- pared to the other arrows (i.e., incongruent trial). Participants are instructed to indicate the pointing direction of the target cue as fast and accurately as possible via a button press on the keyboard with the respective index finger (right index finger for right-pointing target cue; left index finger for left-pointing target cue). Participants receive direct written feedback on the screen for an incorrect or too slow (> 1000 ms) response. After each of five task runs, participants receive feedback about the percentage of correct responses within that run and their average reaction time displayed on the screen. Impor- tant outcomes are the reaction time and accuracy differences between congruent and incongruent task trials, between aversive and neutral trial pictures, as well as the interaction of both (congruency x valence); adapted from Stahl et al. [69] Positivity bias Information processing biases favoring positive versus negative information in attention and interpretation will be assessed with a visual probe task (VPT; [70]) and an ambiguous cue task (ACT; a variant of the task paradigm described in Schick et al. 2013 [71], with visual instead of auditory stimulus material), respectively. In the VPT, participants respond to abstract probe stimuli following the presentation of emotional faces (happy, fearful, and neutral). Positivity biases in atten- tion are inferred from accelerated responses to probes that replace happy as opposed to neutral or negative faces. In the ACT, participants learn to associate two visual cues (e.g., a long and a short bar) with positive vs. negative monetary con- sequences. In the test phase, participants are presented with ambiguous cues (bars of medium length). Responses indicate an individual tendency to interpret ambiguous information as positive or negative 1 3 1042 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 Table 1 (continued) Neuropsychological tests Resilience mechanism Task description Volitional emotion regulation Participants are presented with pictures of differing emotional valence (i.e., aversive and neutral) from the International Affective Picture Set (IAPS). For each picture, participants receive one of three instructions on screen: regard the picture, reappraise (i.e., situation-focused reappraisal), or dissoci- ate. In the regarding condition, participants are expected to carefully look at the picture, take in all its details. In the reappraise condition, participants are asked to change their appraisal of the presented picture scene to regulate their emo- tions, e.g., by telling themselves that the presented picture is just a scene performed by actors. The dissociation condition is another way of regulating emotions, in which participants are asked to distance themselves actively from the picture content, e.g., by making themselves aware that they do not know the displayed people in the picture. After each picture presentation, participants are asked to rate the intensity of their feeling at that moment as fast as possible on a visual analogue scale from very week to very strong. Participants undergo a short instruction phase with example pictures to get familiar with the different emotion regulation strategies. Main outcomes are differences in the emotion ratings and reaction times and electromyographic (EMG) activity between task conditions; established by Schönfelder et al. [72, 73]. Before the experiment starts, three electrodes are placed on the fore- head of the subject for EMG recordings. Two electrodes are placed above the left eyebrow for corrugator muscular activ- ity assessment, while the ground electrode is placed close to the hairline, above all facial muscles (gel-filled electrodes, B iopac® Systems, Inc.) Differential fear conditioning (discrimination) and Classical fear conditioning task, using two different geometric extinction figures as CS + and CS −, respectively, which are counter- balanced either a square or a diamond shape. The CS + is paired with an aversive UCS [i.e., electrodermal stimulation; Digitimer DS7A(CE)] in 50% of all presentations during the acquisition phase by a pain electrode attached to the back of the right hand. Before the acquisition phase, participant’s individual pain threshold is calibrated to reach a pain level that is higher than six on a scale from 0 (“I do not feel anything”) to 10 (“The strongest pain I can imagine being applied with such an electrode”). After each CS + or CS- presentation, participants are asked to rate their level of anxi- ety, fear or tension as fast as possible on a visual analogue scale from “not at all” to “very much”. During extinction, the CS + is never coupled with the US. After the experiment, par- ticipants are asked, which symbol was coupled with the pain stimulation, to make sure that they learned the CS + UCS pairing. During the experiment, participant’s skin conduct- ance rate (SCR) is measured with two electrodes attached to the palm of the left hand (Biopac® Systems, Inc.) Notes: B baseline, F follow-up at main assessments every 18 months; 3m = interim analyses every 3 months; #I = number of total items in a detailed assessment of bodily composition and several Neuropsychiatric Interview (M.I.N.I.) [16] is conducted physical fitness components. This part is optional for the again, to test for potential current mental disorders. If participants (see supplements for details). screened positively, subjects are not excluded from the B1/T6 and B2/T12, day 1 (approx. 40 min: The pro- study; however, trained staff decides in joint consultation cedure for these measurement time points substantially with the participant, whether the participant is stable enough matches the one described for day 1 of B0. The International to complete the whole assessment. Nevertheless, referral to 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1043 the outpatient departments of the psychiatric departments Data management for further diagnosis and treatment will be offered for posi- tively screened subjects. Participants are kept in the study Data collected via the online assessment application (Secu- to follow-up on the possible recovery from these mental ill- Trial database) (see above) are double-checked for consist- nesses and to investigate the skills, traits, and/or external fac- ency and plausibility. In case of missing, inconsistent or tors (e.g., psychotherapy and hospital treatment) that might implausible data, participants are contacted by the study have helped them recover. Regarding biosamples, only one assistants. Furthermore, the SecuTrial database fulfils all blood tube for epigenetic markers is taken and participants requirements regarding data storage and protection accord- are provided with one tube for the stool sample at B1/T6 ing to national laws. Subproject-specific data (i.e., neu- and packing material for hair samples for the following five ropsychological and physiological data) will be entered into measurement time points (3, 6, 9, 12, and 15 months). sub-databases of the central Z03 database, designated to the B1/T6 and B2/T12, day 2 (180 min) The same procedure specific subproject. Access to these sub-databases can only as described for day 2 of the baseline (B0/T0) is repeated. be granted by the leading principal investigators and very Of note, in Frankfurt, the two described assessment days few assigned staff members and are only made available for are conducted in 1 day, due to organizational reasons. Still, the principal investigators of the specific subproject. the questionnaires have to be filled out within 7 days. Fur- thermore, participants are provided with shipping material Planned statistical analyses for the first stool sample at baseline. The longitudinal procedures allow us to link individual prop- erties, collected during baseline assessments on behavioral, Interim online stressor monitoring (T1–T5, T7–T11) biological, and neuropsychological levels, to stress reactivity in a longitudinal matter. By this, resilience processes can be In between the main assessments on-site, participants are identified. Resilience will be indexed by the reactivity of asked to report their individual mental health status (GHQ- individuals’ mental health to stressors during 3-month time 28) online, as well as individual exposures to life stressors intervals in a ‘stressor reactivity’ (SR) score, derived using every 3 months. Here, macro stressors, such as critical or a residualization approach, previously introduced by Kalisch major life events (CLE) and incidents of potentially trau- et  al. [11], which investigates the relationship between matizing events (PTE), as well as microstressors, more stressors, operationalized by a combined score of daily precisely daily hassles (DH) are assessed, as described in hassles and life events over time, against general health, detail in the procedure section and supplementary material. investigated using the GHQ score over time. The SR scores Additionally, participants send back hair samples (T1–T5, can then be calculated using a sliding window approach of T7–T11) as well as gut samples (T1) via mail. overlapping time windows to reduce data loss, which reflects intra-individual temporal variability in resilience. We will Fig. 2 Flow chart of sample recruitment 1 3 1044 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 investigate homeostatic adaptation, testing whether a poten- Baseline data of recruited participants tial resilience mechanism can satisfactorily predict SR over a longer period of time. Furthermore, we will investigate For the resilience assessment, in total, a sample of 1255 possible allostatic adaptations, which are hypothesized to healthy subjects from the Rheine-Main region spanning take place when resilience mechanisms need to change or from Mainz (n = 624) to Frankfurt (n = 631) were enrolled, be adapted for a system to stay resilient, because the stressor of which 1191 subjects completed at least 50% of the first exposure temporarily exceeds the system’s capacity. For the baseline assessment (B0/T1) (see Fig. 2). Blood for DNA examination of allostatic adaption, changes in neuropsycho- isolation has been acquired from n = 1,009 participants, logical performance over time are assumed to be crucial. For stool samples for microbiome analyses from n = 1,041 more detailed information, we refer to Kalisch et al. [9, 11]. Table 2 Baseline data of the Variable n Percentage Range LORA study sample (N = 1191) Gender  Female 783 65.9  Male 406 34.1 Age (M/SD) total 1188 28.59 (7.96) 18–50 < 20 years 63 5.30  20–29 years 724 60.94  30–39 years 246 20.71 > 40 years 155 13.05 Nationality  German 1083 91.86  Other European countries 51 4.32  Others (%) 45 3.82 Marital status  Non-married 867 80.50  Married 182 16.90  Separated 9 0.84  Divorced 16 1.49  Widowed 3 0.28 Highest educational achievement  No school-leaving qualification 1 0.09  School-leaving certificate 2 0.19  Certificate of Secondary Education 29 2.69  School-leaving examination 420 38.92  Completed vocational training 147 13.62  University degree 480 44.49 Employment  Full time 342 31.78  Part time 131 12.17  Part time due to health issues 3 0.28  No employment due to reasons other than health issues 24 2.22  No employment due to health issues 2 0.19  Currently obtaining an education 574 53.35  Number of previous life events (lifetime), M(SD) 1188 11.81 (7.14) 0–39  Number of daily hassles (past 7 days), M(SD) 1149 63.66 (27.14) 0–175  GHQ, overall, M(SD) 1183 16.55 (7.62) 0–49  BRS score, M(SD) 1182 3.76 (0.67) 1–5  PSS score, M(SD) 1186 12.46 (5.74) 0–31 Notes: Percentage based on valid data; mean and standard deviation based on all obtained data, extreme outliers excluded 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1045 participants, and hair for cortisol determination from n = 927 extreme outliers (± 4 or more standard deviations of the participants at baseline. mean), participants reported a mean of 11 major life events In the following, we describe the baseline data regard- during lifetime (Fig. 3a). Furthermore, the number of expe- ing outcome-based resilience measures and the assessment rienced life events correlated positively with participant’s of perceived stress and stressors. Descriptive demographic age (r = 0.36, p < 0.001). The median number of chronic and statistics of the sample is shown in Table 2. Participants’ daily hassles was 60, with a mean = 63.66 (Fig. 3b). On aver- age ranged from 18 to 50 years and the sample is biased age, reported daily hassles equal almost ten hassles per day. towards females (66%). Although 8% of the sample partici- In the self-assessment test of perceived stress (PSS-10), most pants are of non-German nationality, all of them have suf- participants indicated a stress level of 12 (median = 12), ficient knowledge of the German language, as is inferred which can be considered as rather low; 33.6% report to be from the screening interview and the interactions during the moderately-to-highly stressed. assessment. A considerably high number of participants are Reported psychological symptoms at baseline, assessed non-married (80%), most likely due to their rather young by the GHQ-28, were non-normally distributed, with posi- age. The overall education level can be considered as being tive skewedness of 1.49 (SE = 0.07) and kurtosis of 1.45 rather high, since nearly half of the sample (44.5%) holds (SE = 0.14). As shown in Fig. 3c, 993 participants reported a university degree. More than half (53.4%) of the B0/T0 symptoms below the threshold of 23/24 points [19]. Of note, sample participants are still obtaining a degree at the time the 190 (14%) subjects scoring above the diagnostic thresh- of the B0/T0 measurement. old did not fulfil the criteria of a mental disorder according Based on all data from the baseline assessment (see Sup- to the initial M.I.N.I. assessment. plement for detailed description of the scoring), excluding Fig. 3 Frequency of previous life events, chronic and daily hassles, and mental health 1 3 1 046 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 Current and future work have, e.g., shown that an increase in the glucocorticoid recep- tor (encoded by NR3C1) promoter methylation later leads to As of July 2019, the first baseline assessment (B0/T0) has higher stress resilience, pointing to an allostatic adaption of been completed for all participants at both sites. Interim the stress axis as a consequence of life events [80]. These and online stressor monitoring, as well as the second baseline other studies provide first clues on how the genetic makeup measurement (B1/T6) are ongoing. The third baseline meas- might interact with the environment to affect resilience out- urement (B2/T12), which is 3 years post-study onset, will be comes. Furthermore, there might be genetic variants that assessed in the first subjects in Mainz and Frankfurt in Feb- could more directly influence adaptation processes to stress- ruary 2020. The unique study design and analysis scheme, as ors [81]. To this end, DNA is sampled in LORA to generate outlined in Fig. 1 will be continued. We plan to follow up the genome-wide SNP analyses and epigenome-wide analyses to 1191 participants enrolled at B0/T0 (baseline) for another further examine their link with resilience mechanisms. 3 years (up to early B4/T24). In the LORA study, also data concerning physical fitness levels and body composition are collected, since there is Discussion, limitations, and outlook plenty of evidence that physical fitness, achieved through regular physical exercise, yields physical and mental health We have postulated that resilience is not simply the absence benefits by influencing stress responses [82, 83]. Further- of mental health problems, but rather a process that can be more, Mujica-Parodi and colleagues [84] showed that operationalized as the amount of stress and daily hassles a per- increased body fat was related to elevated cortisol reactiv- son encounters over time in relationship to the general health ity and decreased cognitive performance, particularly spa- outcome that person shows [2].This calls for the use of lon- tial processing, selective attention, and working memory. gitudinal approaches to investigate resilience mechanisms in As such, body fat percentage can also have an impact on more depth. The LORA study uses a unique design to assess stress responsivity and cognitive performance, rendering it resilience over a time period of at least 3 years, being able to a worthwhile resilience mechanism to investigate. observe resilience mechanisms, while they occur in response As is known from recent studies, the gut–brain axis also to modern-life stressors. This is done by extensively capturing plays an important role in stress responses. For example, participant’s stressor load with intermediate online stressor stress was shown to reduce the bacterial levels in the gut monitoring every three months, representing a very high flora of a student sample during exam weeks, indicating sampling rate. This monitoring not only assesses the influ- an influence of stressor exposure on the gastrointestinal ence of life events, but also captures modern every-day life microflora [85]. Hence, the stool samples collected in the stressors, the so-called daily hassles, assessed with the Mainz present study can give important information on the influ- Inventory of Microstressors (MIMIS; [25]), giving a good ences of stress on a person’s microbiome and how a certain overview of minor and major stressors, together with their microbiota composition determines stress responses in the temporal extend. The stressor monitoring includes also hair individual. cortisol samples, resulting in a more objective way to capture A total of 1255 participants have been recruited in the undergone stress and activation of the hypothalamic–pitui- LORA study, which exceeds the originally planned 1200 tary–adrenal (HPA) axis over the last 3 months [79]. participants. Of those enrolled participants, 1191 partici- Moreover, several cognitive abilities, which are assumed pants have completed more than 50% of the assessment at to be affected under stress, are tested with a neuropsycho- baseline. Slightly more women are enrolled in the study logical test battery during the baseline assessment time (65.9%) and most participants are rather highly educated, points every 18 months. The repeated application of this with 44.9% having a university degree and more than half neuropsychological test battery in the LORA study will give of the sample currently obtaining one. However, highly new insights into the duration of these influences, possible educated samples are a phenomenon commonly observed interindividual differences, and are a proxy for the under- in large-scale studies, such as the present one [86]. Uni- lying neurobiological processes taking place in resilience. versity students are a quite homogenous group of people. Most importantly, this neuropsychological battery may shed They are easy to recruit and potentially have a higher eco- light on the resilience mechanisms taking place in between nomic motivation to participate in studies and also have assessment time points. sufficient time to take part in longitudinal studies, like the Resilience mechanisms might also include alterations of present one. However, they might not be representative for gene expression, e.g., via epigenetic modifications such as the world population [87]. Therefore, the results should be DNA methylation. Thereby the environment may interact interpreted with caution. It is unclear whether students are a with gene regulatory networks, such as the glucocorticoid group of people who are usually exposed to relatively small system. Studies in rats and postmortem studies in humans amounts of stress, or even to a lot of stress and if they have 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1047 better coping mechanisms compared to the world popula- applies a new and more fine-grained approach to investigate tion. However, the rather low amount of perceived stress on resilience. While the previous studies have mainly focused the PSS-10 in the present study infers a rather reduced level on resilience by assessing participant’s health outcomes (i.e., of stress exposure in the current sample compared to other stress-related psychiatric disorders vs. no disorder), linking studies (e.g., [88]). Participants show a medium amount of them to stressors retrospectively, the presented study uses a previous life events, with a mean = 11.81, and a rather low forward approach by observing stressors and directly assess- number of daily hassles with on average almost 64 hassles ing their influence on the human organism. This is done by (mean = 63.66). Participants’ general health was good, as investigating many distinct domains with respect to their indicated by a GHQ mean score of 16.55, with none of the link with resilience and using multiple techniques, such as participants showing any psychiatric disorders on axis I, biological samples, neuropsychological performance, self- as assessed on the M.I.N.I. interview [16]. The mean BRS rating questionnaires, diagnostic interviews, and individual score was within the range of previously reported BRS fitness. Therefore, the LORA study will be able to give infor- means in comparable German populations (M = 3.58 and mation on how these different domains interact and influence M = 3.37; [31] and M = 3.35; [90]). Hence, the self-reported each other with regard to resilience outcomes. Furthermore, ability to bounce back and recover from stress in the current through the application of more objective measures, such as sample was comparable to previous observations. biological samples, the presented project can advance resil- Several possible limitations of the project have to be ience research. In sum, the LORA study uses a promising considered. First, as with all longitudinal projects, there is approach to shed light on the mechanisms applied in the always some amount of drop-out over time, especially for resilience process. studies running over several years such as the present one. However, in the presented project, the drop-out rate is rather Acknowledgements Open Access funding provided by Projekt DEAL. low with 15.3% from the first baseline to the second base- This work was funded by the German Research Foundation (DFG CRC 1193, subprojects B01, C01, C04, C05, C07, Z03), the Stiftung Rhein- line assessment and an overall drop-out rate of 21% over all land-Pfalz für Innovation (MARP program, No 961-386261/1080), the time points that are currently assessed, undershooting the Ministry of Science of the state of Rhineland-Palatinate (DRZ pro- expected overall drop-out rate of 25%. Second, due to the gram), and the European Union’s Horizon 2020 research and innova- vast amount of data collected in different modalities, the tion program (grant agreements No 777084, 667302 and 728018). We would like to thank all the collaborators for their knowledgeable input project places a rather high burden on the participants. As and expertise throughout all the phases of the project and for their such, sampling biases, such as a self-selection bias, can be thorough revision of this manuscript. We are grateful to all the par- expected as well as missing or incomplete data, especially ticipants who took part in the LORA study and the student assistants, during the interim online stressor monitoring. Not all par- laboratory staff, and lab coordinators who supported the LORA study over the years. ticipants are available over such a long time period or able to come to the baseline measurements during the week. This Compliance with ethical standards might result in a rather young sample, consisting of par- ticipants who are not working full time yet. Although the Conflict of interest The authors declare that they have no conflict of present study sample consists of a rather high amount of interest. young and highly educated participants, there is still a good variance in the sample, assuring a generalizability of the Ethical approval The manuscript does not contain clinical studies or patient data. All procedures were approved by the respective Ethical findings to the general population. Also, such small sam- Committees in Mainz (registration number: 837.105.16(10424)) and pling biases are rather often in longitudinal studies. Drop- Frankfurt (registration number: 244/16), complied with the Declaration outs and missing data are reduced by a repeated reminder of Helsinki (latest version) and written informed consent was obtained scheme for online stressor monitorings via e-mail, regular from all participants. booster mails to participants, thanking them for their study participation, give-aways with the LORA logo printed on Open Access This article is licensed under a Creative Commons Attri- them. Furthermore, participants will be notified of publica- bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long tions of resilience research to become aware of the impact as you give appropriate credit to the original author(s) and the source, of their contribution to science. provide a link to the Creative Commons licence, and indicate if changes In sum, the LORA study is a unique starting point for a were made. The images or other third party material in this article are more detailed investigation into resilience mechanisms, in included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in that it investigates these mechanisms, while they actually the article’s Creative Commons licence and your intended use is not occur, rather than in a retrospective fashion. As such, the full permitted by statutory regulation or exceeds the permitted use, you will process, from the occurrence of stressors to a possible recov- need to obtain permission directly from the copyright holder. To view a ery from them, can be observed online. In addition, by inves- copy of this licence, visit http://creati vecom mons. org/licens es/by/4.0/. tigating healthy participants over time, the presented project 1 3 1048 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 References 1 8. 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Ment Health Phys Act 8:1–7. https: //doi.org/10.1016/j. mhpa.2014.10.001 1 3 European Archives of Psychiatry and Clinical Neuroscience (2021) 271:1035–1051 1051 Affiliations A. Chmitorz1,2 · R. J. Neumann3 · B. Kollmann1,4  · K. F. Ahrens3 · S. Öhlschläger3 · N. Goldbach3 · D. Weichert1 · A. Schick4,5,6 · B. Lutz4,7 · M. M. Plichta3 · C. J. Fiebach8,9 · M. Wessa4,10 · R. Kalisch4,5 · O. Tüscher1,4 · K. Lieb1,4 · A. Reif3 1 Department of Psychiatry and Psychotherapy, University 6 Department of Public Mental Health, Central Institute Medical Center Mainz, Mainz, Germany of Mental Health, Medical Faculty Mannheim, Heidelberg 2 Faculty of Social Work, Health Care and Nursing University, Mannheim, Germany Science, Esslingen University of Applied Sciences, 7 Department of Physiological Chemistry, University Medical Esslingen am Neckar, Germany Center Mainz, Mainz, Germany 3 Department of Psychiatry, Psychosomatic Medicine 8 Department of Psychology, Goethe University Frankfurt, and Psychotherapy, University Hospital Frankfurt, Frankfurt, Frankfurt am Main, Germany Germany 9 Brain Imaging Center, Goethe University, Frankfurt, 4 Leibniz Institute for Resilience Research (LIR), Wallstraße 7, Germany Mainz 55122, Deutschland 10 Department of Clinical Psychology and Neuropsychology, 5 Neuroimaging Center (NIC), Focus Program Translational Institute for Psychology, Johannes Gutenberg University Neuroscience (FTN), University Medical Center Mainz, Mainz, Mainz, Germany Mainz, Germany 1 3