ABSTRACT
Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.
ABSTRACT
BACKGROUND: Conduct disorder is associated with the highest burden of any mental disorder in childhood, yet its neurobiology remains unclear. Inconsistent findings limit our understanding of the role of brain structure alterations in conduct disorder. This study aims to identify the most robust and replicable brain structural correlates of conduct disorder. METHODS: The ENIGMA-Antisocial Behavior Working Group performed a coordinated analysis of structural MRI data from 15 international cohorts. Eligibility criteria were a mean sample age of 18 years or less, with data available on sex, age, and diagnosis of conduct disorder, and at least ten participants with conduct disorder and ten typically developing participants. 3D T1-weighted MRI brain scans of all participants were pre-processed using ENIGMA-standardised protocols. We assessed group differences in cortical thickness, surface area, and subcortical volumes using general linear models, adjusting for age, sex, and total intracranial volume. Group-by-sex and group-by-age interactions, and DSM-subtype comparisons (childhood-onset vs adolescent-onset, and low vs high levels of callous-unemotional traits) were investigated. People with lived experience of conduct disorder were not involved in this study. FINDINGS: We collated individual participant data from 1185 young people with conduct disorder (339 [28·6%] female and 846 [71·4%] male) and 1253 typically developing young people (446 [35·6%] female and 807 [64·4%] male), with a mean age of 13·5 years (SD 3·0; range 7-21). Information on race and ethnicity was not available. Relative to typically developing young people, the conduct disorder group had lower surface area in 26 cortical regions and lower total surface area (Cohen's d 0·09-0·26). Cortical thickness differed in the caudal anterior cingulate cortex (d 0·16) and the banks of the superior temporal sulcus (d -0·13). The conduct disorder group also had smaller amygdala (d 0·13), nucleus accumbens (d 0·11), thalamus (d 0·14), and hippocampus (d 0·12) volumes. Most differences remained significant after adjusting for ADHD comorbidity or intelligence quotient. No group-by-sex or group-by-age interactions were detected. Few differences were found between DSM-defined conduct disorder subtypes. However, individuals with high callous-unemotional traits showed more widespread differences compared with controls than those with low callous-unemotional traits. INTERPRETATION: Our findings provide robust evidence of subtle yet widespread brain structural alterations in conduct disorder across subtypes and sexes, mostly in surface area. These findings provide further evidence that brain alterations might contribute to conduct disorder. Greater consideration of this under-recognised disorder is needed in research and clinical practice. FUNDING: Academy of Medical Sciences and Economic and Social Research Council.
Subject(s)
Conduct Disorder , Magnetic Resonance Imaging , Humans , Conduct Disorder/pathology , Conduct Disorder/diagnostic imaging , Male , Female , Adolescent , Child , Cohort Studies , Cerebral Cortex/pathology , Cerebral Cortex/diagnostic imaging , Organ Size , Brain/pathology , Brain/diagnostic imaging , Young Adult , Amygdala/pathology , Amygdala/diagnostic imagingABSTRACT
Conduct disorder (CD) is characterised by persistent antisocial and aggressive behaviour and typically emerges in childhood or adolescence. Although several authors have proposed that CD is a neurodevelopmental disorder, very little evidence is available about brain development in this condition. Structural brain alterations have been observed in CD, and some indirect evidence for delayed brain maturation has been reported. However, no detailed analysis of age-related changes in brain structure in youth with CD has been conducted. Using cross-sectional MRI data, this study aimed to explore differences in brain maturation in youth with CD versus healthy controls to provide further understanding of the neurodevelopmental processes underlying CD. 291 CD cases (153 males) and 379 healthy controls (160 males) aged 9-18 years (Mage = 14.4) were selected from the European multisite FemNAT-CD study. Structural MRI scans were analysed using surface-based morphometry followed by application of the ENIGMA quality control protocols. An atlas-based approach was used to investigate group differences and test for group-by-age and group-by-age-by-sex interactions in cortical thickness, surface area and subcortical volumes. Relative to healthy controls, the CD group showed lower surface area across frontal, temporal and parietal regions as well as lower total surface area. No significant group-by-age or group-by-age-by-sex interactions were observed on any brain structure measure. These findings suggest that CD is associated with lower surface area across multiple cortical regions, but do not support the idea that CD is associated with delayed brain maturation, at least within the age bracket considered here.
Subject(s)
Brain , Conduct Disorder , Magnetic Resonance Imaging , Humans , Conduct Disorder/diagnostic imaging , Conduct Disorder/pathology , Adolescent , Male , Child , Female , Brain/pathology , Brain/diagnostic imaging , Brain/growth & development , Cross-Sectional Studies , Age FactorsABSTRACT
Previous research on the neurobiological bases of resilience in youth has largely used categorical definitions of resilience and voxel-based morphometry methods that assess gray matter volume. However, it is important to consider brain structure more broadly as different cortical properties have distinct developmental trajectories. To address these limitations, we used surface-based morphometry and data-driven, continuous resilience scores to examine associations between resilience and cortical structure. Structural MRI data from 286 youths (Mage = 13.6 years, 51% female) who took part in the European multi-site FemNAT-CD study were pre-processed and analyzed using surface-based morphometry. Continuous resilience scores were derived for each participant based on adversity exposure and levels of psychopathology using the residual regression method. Vertex-wise analyses assessed for correlations between resilience scores and cortical thickness, surface area, gyrification and volume. Resilience scores were positively associated with right lateral occipital surface area and right superior frontal gyrification and negatively correlated with left inferior temporal surface area. Moreover, sex-by-resilience interactions were observed for gyrification in frontal and temporal regions. Our findings extend previous research by revealing that resilience is related to surface area and gyrification in frontal, occipital and temporal regions that are implicated in emotion regulation and face or object recognition.
Subject(s)
Resilience, Psychological , Adolescent , Humans , Female , Male , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Temporal Lobe , Magnetic Resonance Imaging/methods , Gray Matter/diagnostic imagingABSTRACT
There is increasing evidence that resilience in youth may have a neurobiological basis. However, the existing literature lacks a consistent way of operationalizing resilience, often relying on arbitrary judgments or narrow definitions (e.g., not developing PTSD) to classify individuals as resilient. Therefore, this study used data-driven, continuous resilience scores based on adversity and psychopathology to investigate associations between resilience and brain structure in youth. Structural MRI data from 298 youth aged 9-18 years (Mage = 13.51; 51% female) who participated in the European multisite FemNAT-CD study were preprocessed using SPM12 and analyzed using voxel-based morphometry. Resilience scores were derived by regressing data on adversity exposure against current/lifetime psychopathology and quantifying each individual's distance from the regression line. General linear models tested for associations between resilience and gray matter volume (GMV) and examined whether associations between resilience and GMV differed by sex. Resilience was positively correlated with GMV in the right inferior frontal and medial frontal gyri. Sex-by-resilience interactions were observed in the middle temporal and middle frontal gyri. These findings demonstrate that resilience in youth is associated with volume in brain regions implicated in executive functioning, emotion regulation, and attention. Our results also provide evidence for sex differences in the neurobiology of resilience.
Subject(s)
Resilience, Psychological , Adolescent , Humans , Female , Male , Brain/diagnostic imaging , Brain/pathology , Gray Matter/diagnostic imaging , Gray Matter/pathology , Prefrontal Cortex/pathology , Frontal Lobe/pathology , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Childhood maltreatment is common in youths with conduct disorder (CD), and both CD and maltreatment have been linked to neuroanatomical alterations. Nonetheless, our understanding of the contribution of maltreatment to the neuroanatomical alterations observed in CD remains limited. We tested the applicability of the ecophenotype model to CD, which holds that maltreatment-related psychopathology is (neurobiologically) distinct from psychopathology without maltreatment. METHODS: Surface-based morphometry was used to investigate cortical volume, thickness, surface area, and gyrification in a mixed-sex sample of participants with CD (n = 114) and healthy control subjects (HCs) (n = 146), ages 9 to 18 years. Using vertexwise general linear models adjusted for sex, age, total intracranial volume, and site, the control group was compared with the overall CD group and the CD subgroups with (n = 49) versus without (n = 65) maltreatment (assessed by the Children's Bad Experiences interview). These subgroups were also directly compared. RESULTS: The overall CD group showed lower cortical thickness in the right inferior frontal gyrus. CD youths with a history of maltreatment showed more widespread structural alterations relative to HCs, comprising lower thickness, volume, and gyrification in inferior and middle frontal regions. Conversely, CD youths with no history of maltreatment only showed greater left superior temporal gyrus folding relative to HCs. When contrasting the CD subgroups, those with maltreatment displayed lower right superior temporal gyrus volume, right precentral gyrus surface area, and gyrification in frontal, temporal, and parietal regions. CONCLUSIONS: Consistent with the ecophenotype model, findings indicated that CD youths with versus without maltreatment differ neurobiologically. This highlights the importance of considering maltreatment history in neuroimaging studies of CD and other disorders.
Subject(s)
Child Abuse , Conduct Disorder , Adolescent , Child , Humans , Magnetic Resonance Imaging/methods , Temporal Lobe/pathology , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/pathologyABSTRACT
BACKGROUND: Previous studies have reported brain structure abnormalities in conduct disorder (CD), but it is unclear whether these neuroanatomical alterations mediate the effects of familial (genetic and environmental) risk for CD. We investigated brain structure in adolescents with CD and their unaffected relatives (URs) to identify neuroanatomical markers of familial risk for CD. METHODS: Forty-one adolescents with CD, 24 URs of CD probands, and 38 healthy controls (aged 12-18), underwent structural magnetic resonance imaging. We performed surface-based morphometry analyses, testing for group differences in cortical volume, thickness, surface area, and folding. We also assessed the volume of key subcortical structures. RESULTS: The CD and UR groups both displayed structural alterations (lower surface area and folding) in left inferior parietal cortex compared with controls. In contrast, CD participants showed lower insula and pars opercularis volume than controls, and lower surface area and folding in these regions than controls and URs. The URs showed greater folding in rostral anterior cingulate and inferior temporal cortex than controls and greater medial orbitofrontal folding than CD participants. The surface area and volume differences were not significant when controlling for attention-deficit/hyperactivity disorder comorbidity. There were no group differences in subcortical volumes. CONCLUSIONS: These findings suggest that alterations in inferior parietal cortical structure partly mediate the effects of familial risk for CD. These structural changes merit investigation as candidate endophenotypes for CD. Neuroanatomical changes in medial orbitofrontal and anterior cingulate cortex differentiated between URs and the other groups, potentially reflecting neural mechanisms of resilience to CD.
Subject(s)
Conduct Disorder , Humans , Adolescent , Conduct Disorder/diagnostic imaging , Genetic Predisposition to Disease , Brain/diagnostic imaging , Brain/pathology , Parietal Lobe/diagnostic imaging , Parietal Lobe/pathology , Temporal Lobe/pathology , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Given the chronic work-related stressors experienced by nursing staff in today's healthcare systems, international evidence suggests an elevated risk of developing stress-related mental symptoms. Therefore, identifying effective methods to foster resilience (i.e., maintenance or fast recovery of mental health despite stressor exposure) seems crucial. To date, little is known about the efficacy of these interventions in nurses. OBJECTIVE: This systematic review aimed at summarizing the evidence on the pre-pandemic efficacy of psychological interventions to foster resilience, to improve mental symptoms and well-being as well as to promote resilience factors in nurses. Based on training programs with evidence for positive effects on resilience and mental health in meta-analyses, we aimed at identifying important and helpful intervention techniques. DESIGN: Systematic review and meta-analyses based on a Cochrane review on pre-pandemic resilience interventions in healthcare professionals. DATA SOURCES: MEDLINE, Embase, CENTRAL and 11 other databases were searched until June 2020 to identify eligible randomized controlled trials. Trial registers, reference lists and contact with authors were additional sources. REVIEW METHODS: Two reviewers independently assessed study eligibility and extracted data. The Cochrane risk of bias assessment tool was used to evaluate the risk of bias of included studies. We conducted random-effects pairwise meta-analyses for five primary outcomes, including resilience. The intervention contents and techniques were narratively synthesized. RESULTS: Of 39,794 records retrieved, 24 studies were included in the review (Nâ¯=â¯1879 randomized participants), 17 in meta-analyses (nâ¯=â¯1020 participants). At post-intervention, we found very-low certainty evidence of moderate effects in favor of resilience training for resilience (standardized mean difference [SMD] 0.39; 95% CI [confidence interval] 0.12-0.66) and well-being (SMD 0.44; 95% CI 0.15-0.72), while there was no evidence of effects on symptoms of anxiety, depression and stress. The improvement of well-being was sustained in the short-term (≤3â¯months), with additional delayed benefits for anxiety and stress. There was no evidence of effects at later follow-ups, with the caveat of only three available studies. Among nine programs with evidence of positive moderate effect sizes, intervention contents included mindfulness and relaxation, psychoeducation, emotion regulation, cognitive strategies, problem-solving and the strengthening of internal and external resources. CONCLUSIONS: Given the chronic stressor exposure in nursing staff, our findings may guide both the design and implementation of nurse-directed resilience interventions. To improve the certainty of evidence, more rigorous high-quality research using improved study designs (e.g., larger sample sizes, longer follow-up periods) is urgently needed. REGISTRATION: PROSPERO 2017 CRD42017082827.
Subject(s)
Nursing Staff , Pandemics , Anxiety/psychology , Humans , Mental Health , Quality of LifeABSTRACT
Attention-Deficit/Hyperactivity Disorder (ADHD) is increasingly viewed as a disorder of brain connectivity. We review connectivity-based theories of ADHD including the default mode network (DMN) interference and multiple network hypotheses. We outline the main approaches used to study brain connectivity in ADHD: diffusion tensor imaging and resting-state functional connectivity. We discuss the basic principles underlying these methods and the main analytical approaches used and consider what the findings have told us about connectivity alterations in ADHD. The most replicable finding in the diffusion tensor imaging literature on ADHD is lower fractional anisotropy in the corpus callosum, a key commissural tract which connects the brain's hemispheres. Meta-analyses of resting-state functional connectivity studies have failed to identify spatial convergence across studies, with the exception of meta-analyses focused on specific networks which have reported within-network connectivity alterations in the DMN and between the DMN and the fronto-parietal control and salience networks. Overall, methodological heterogeneity between studies and differences in sample characteristics are major barriers to progress in this area. In addition, females, adults and medication-naïve/unmedicated individuals are under-represented in connectivity studies, comorbidity needs to be assessed more systematically, and longitudinal research is needed to investigate whether ADHD is characterized by maturational delays in connectivity.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adult , Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Brain/diagnostic imaging , Brain Mapping/methods , Diffusion Tensor Imaging , Female , Humans , Magnetic Resonance Imaging/methods , Neural PathwaysABSTRACT
INTRODUCTION: It is claimed that the coronavirus disease 2019 (COVID-19) pandemic has had a negative impact on mental health. However, to date, prospective studies are lacking. Moreover, it is important to identify which factors modulate the stress response to the pandemic. Previously, sense of coherence (SOC) has emerged as a particularly important resistance factor. OBJECTIVE: This prospective study aimed to assess the impact of the COVID-19 outbreak on mental health and to investigate the ability of pre-outbreak SOC levels to predict changes in psychopathological symptoms. METHODS: This study assessed psychopathological symptoms and SOC before and after the COVID-19 outbreak as well as post-outbreak COVID-19-related traumatic distress in a German-speaking sample (n =1,591). Bivariate latent change score (BLCS) modeling was used to analyze pre- to post-outbreak changes in psychopathological symptoms and the ability of SOC to predict symptom changes. RESULTS: Overall, there was no change in psychopathological symptoms. However, on an individual-respondent level, 10% experienced a clinically significant increase in psychopathological symptoms and 15% met cut-off criteria for COVID-19-related traumatic distress. Using BLCS modeling, we identified a high-stress group experiencing an increase in psychopathological symptoms and a decrease in SOC and a low-stress group showing the reversed pattern. Changes in SOC and psychopathological symptoms were predicted by pre-outbreak SOC and psychopathological symptom levels. CONCLUSIONS: Although mental health was stable in most respondents, a small group of respondents characterized by low levels of SOC experienced increased psychopathological symptoms from pre- to post-outbreak. Thus, SOC training might be a promising approach to enhance the resistance to stressors.
Subject(s)
Behavioral Symptoms/psychology , Coronavirus Infections , Pandemics , Pneumonia, Viral , Sense of Coherence , Stress Disorders, Traumatic/psychology , Adult , Aged , Aged, 80 and over , Behavioral Symptoms/epidemiology , COVID-19 , Female , Follow-Up Studies , Germany/epidemiology , Humans , Male , Mental Health/statistics & numerical data , Middle Aged , Prospective Studies , Public Health/statistics & numerical data , Stress Disorders, Traumatic/epidemiology , Young AdultABSTRACT
BACKGROUND: Hospitals, police stations, and fire departments are highly demanding workplaces. Staff members are regularly exposed to various stressors including traumatic events. Correspondingly, several studies report high rates of mental health issues among these occupations. Nevertheless, despite these challenging circumstances, some staff members manage to sustain their mental health. The current study is the first to investigate three health-promoting factors simultaneously among three different, highly demanding occupations. METHODS: The present cross-sectional survey investigated health-promoting factors (sense of coherence - SOC, trait-resilience, locus of control - LOC) and mental health outcomes (general psychopathological symptom burden, posttraumatic stress, burnout) in medical staff (n = 223), police officers (n = 257), and firefighters (n = 100). RESULTS: Among all occupations, SOC, trait-resilience, and an internal LOC were negatively associated with general psychopathological symptoms, posttraumatic stress, and burnout symptoms. By contrast, all these outcome measures were positively correlated with an external LOC. Multiple regression models including all health-promoting factors explained 56% of the variance in general psychopathological symptoms and 27% in posttraumatic stress symptoms. Among all occupations, SOC was the strongest predictor of both general psychopathological symptom burden and posttraumatic stress symptoms. Multigroup path analyses revealed minor differences across occupations, mainly driven by a stronger influence of LOC in police officers. CONCLUSION: Across all occupations, SOC was identified as the most important health-promoting factor. Future longitudinal studies should further examine the causal link between health-promoting factors and mental distress in different workplaces. Such studies will also allow for further development and evaluation of resilience promoting programs.
Subject(s)
Burnout, Professional , Occupations , Stress Disorders, Post-Traumatic , Adult , Burnout, Professional/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Mental Health , Risk , Stress Disorders, Post-Traumatic/diagnosis , Stress Disorders, Post-Traumatic/epidemiology , Surveys and QuestionnairesABSTRACT
Numerous studies have shown that post-learning sleep enhances visual episodic recognition memory. However, it remains unclear whether this consolidation benefit is moderated by the emotional valence of the learned material. To clarify whether sleep selectively enhances memory for emotional material, we conducted a meta-analysis including N = 1059 post-sleep/wake observations. Overall, our results do not support this hypothesis. When only studies with a sleep group/wake group comparison were included in the analysis (k = 22), the retention advantage for emotional (negative/positive) over neutral material was not significantly different between sleep and wake groups. When studies without wake groups were included in the analysis after statistical estimation of wake-group parameters, the retention advantage for emotional material was significantly larger in wake groups than in sleep groups (k = 34). Interestingly, however, an additional analysis of eight studies investigating the selective effects of rapid-eye-movement sleep and slow-wave sleep on post-interval emotional memory provided evidence for a selective enhancement of emotional over neutral memory performance after rapid-eye-movement sleep compared to slow-wave sleep. These findings suggest that sleep does not generally enhance visual recognition memory for emotional stimuli. However, the result pattern is consistent with the idea that specific sleep stages preferentially enhance consolidation of emotional and neutral material, respectively.
Subject(s)
Emotions , Memory Consolidation , Memory/physiology , Sleep, REM/physiology , Sleep/physiology , Electroencephalography , Humans , Sleep, Slow-WaveABSTRACT
Background: Hospitals, and particularly intensive care units (ICUs), are demanding and stressful workplaces. Physicians and nurse staff are exposed to various stressors: emergency situations, patients' deaths, and team conflicts. Correspondingly, several studies describe increased rates of PTSD symptoms and other mental health problems in hospital staff. Therefore, it is important to identify factors that lower the risk of psychopathological symptoms. High levels of sense of coherence (SOC) and general resilience as well as an internal locus of control (LOC) have already been identified as important health-benefitting factors in medical staff. The current study aimed to evaluate their unique impact in an ICU and an anesthesiology unit. Method: The cross-sectional online survey investigated SOC, LOC, general resilience, general mental health problems as well as PTSD symptoms in nurses and physicians within an ICU and an anesthesiology unit (N = 52, 65.4% female). General mental health problems were assessed using the ICD-10-Symptom-Rating (ISR) and PTSD symptoms were measured using the PTSD Checklist for DSM-5 (PCL-5). The Sense of Coherence Scale (SOC-L9) assessed SOC, the Resilience Scale (RS-11) measured general resilience, and LOC was determined using a 4-item scale for the assessment of control beliefs (IE-4). Results: As expected, SOC, r = -0.72, p < 0.001, general resilience, r = -0.46, p < 0.001, and internal LOC, r = -0.51, p < 0.001, were negatively correlated with general mental health problems while an external LOC showed a positive association, r = 0.35, p = 0.010. However, in a multiple regression model, R 2 = 53.9%, F (4, 47) = 13.73, p < 0.001, only SOC significantly predicted general mental health problems by uniquely accounting for 13% of the variance. For PTSD symptoms, which were highly correlated with general mental health problems, a similar pattern of results was found. Conclusion: SOC was found to be the most important correlate of both general mental health problems and PTSD symptoms in an ICU and an anesthesiology unit. Thus, if further evidenced by longitudinal studies, implementing interventions focusing on an enhancement of SOC in training programs for ICU and anesthesiology unit staff might be a promising approach to prevent or reduce psychopathological symptoms.
ABSTRACT
BACKGROUND: Specific phobias are among the most common anxiety disorders. Exposure therapy is the treatment of choice for specific phobias. However, not all patients respond equally well to it. Hence, current research focuses on therapeutic add-ons to increase and consolidate the effects of exposure therapy. One potential therapeutic add-on is biofeedback to increase heart rate variability (HRV). A recent meta-analysis shows beneficial effects of HRV biofeedback interventions on stress and anxiety symptoms. Therefore, the purpose of the current trial is to evaluate the effects of HRV biofeedback, which is practiced before and utilized during exposure, in spider-fearful individuals. Further, this trial is the first to differentiate between the effects of a HRV biofeedback intervention and those of a low-load working memory (WM) task. METHODS: Eighty spider-fearful individuals participate in the study. All participants receive a training session in which they practice two tasks (HRV biofeedback and a motor pseudo-biofeedback task or two motor pseudo-biofeedback tasks). Afterwards, they train both tasks at home for 6 days. One week later, during the exposure session, they watch 16 1-min spider video clips. Participants are divided into four groups: group 1 practices the HRV biofeedback and one motor pseudo-task before exposure and utilizes HRV biofeedback during exposure. Group 2 receives the same training, but continues the pseudo-biofeedback task during exposure. Group 3 practices two pseudo-biofeedback tasks and continues one of them during exposure. Group 4 trains in two pseudo-biofeedback tasks and has no additional task during exposure. The primary outcome is fear of spiders (measured by the Fear of Spiders Questionnaire and the Behavioral Approach Test). Secondary outcomes are physiological measures based on electrodermal activity, electrocardiogram and respiration. DISCUSSION: This RCT is the first one to investigate the effects of using a pre-trained HRV biofeedback during exposure in spider-fearful individuals. The study critically contrasts the effects of the biofeedback intervention with those of pseudo-tasks, which also require WM capacity, but which do not have a physiological base. If HRV biofeedback is effective in reducing fear of spiders, it would represent an easy-to-use tool to improve exposure-therapy outcomes. TRIAL REGISTRATION: Deutsches Register Klinischer Studien, DRKS00012278 . Registered on 23 May 2017, amendment on 5 October 2017.