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Startseite > Forschung > Publikationen / Publications > Nees

# Prof. Dr. rer. nat. Nees

#### 2021

Albaugh, M. D., Ottino-Gonzalez, J., Sidwell, A., Lepage, C., …, Nees, F., …, IMAGEN Consortium, & Garavan, H. (2021). Association of Cannabis Use During Adolescence With Neurodevelopment. JAMA Psychiatry. PMID:34132750, doi:10.1001/jamapsychiatry.2021.1258.

Importance Animal studies have shown that the adolescent brain is sensitive to disruptions in endocannabinoid signaling, resulting in altered neurodevelopment and lasting behavioral effects. However, few studies have investigated ties between cannabis use and adolescent brain development in humans. Objective To examine the degree to which magnetic resonance (MR) imaging-assessed cerebral cortical thickness development is associated with cannabis use in a longitudinal sample of adolescents. Design, Setting, and Participants Data were obtained from the community-based IMAGEN cohort study, conducted across 8 European sites. Baseline data used in the present study were acquired from March 1, 2008, to December 31, 2011, and follow-up data were acquired from January 1, 2013, to December 31, 2016. A total of 799 IMAGEN participants were identified who reported being cannabis naive at study baseline and had behavioral and neuroimaging data available at baseline and 5-year follow-up. Statistical analysis was performed from October 1, 2019, to August 31, 2020. Main Outcomes and Measures Cannabis use was assessed at baseline and 5-year follow-up with the European School Survey Project on Alcohol and Other Drugs. Anatomical MR images were acquired with a 3-dimensional T1-weighted magnetization prepared gradient echo sequence. Quality-controlled native MR images were processed through the CIVET pipeline, version 2.1.0. Results The study evaluated 1598 MR images from 799 participants (450 female participants [56.3%]; mean [SD] age, 14.4 [0.4] years at baseline and 19.0 [0.7] years at follow-up). At 5-year follow-up, cannabis use (from 0 to >40 uses) was negatively associated with thickness in left prefrontal (peak: t785 = -4.87, cluster size = 1558 vertices; P = 1.10 × 10-6, random field theory cluster corrected) and right prefrontal (peak: t785 = -4.27, cluster size = 1551 vertices; P = 2.81 × 10-5, random field theory cluster corrected) cortices. There were no significant associations between lifetime cannabis use at 5-year follow-up and baseline cortical thickness, suggesting that the observed neuroanatomical differences did not precede initiation of cannabis use. Longitudinal analysis revealed that age-related cortical thinning was qualified by cannabis use in a dose-dependent fashion such that greater use, from baseline to follow-up, was associated with increased thinning in left prefrontal (peak: t815.27 = -4.24, cluster size = 3643 vertices; P = 2.28 × 10-8, random field theory cluster corrected) and right prefrontal (peak: t813.30 = -4.71, cluster size = 2675 vertices; P = 3.72 × 10-8, random field theory cluster corrected) cortices. The spatial pattern of cannabis-related thinning was associated with age-related thinning in this sample (r = 0.540; P < .001), and a positron emission tomography-assessed cannabinoid 1 receptor-binding map derived from a separate sample of participants (r = -0.189; P < .001). Analysis revealed that thinning in right prefrontal cortices, from baseline to follow-up, was associated with attentional impulsiveness at follow-up. Conclusions and Relevance Results suggest that cannabis use during adolescence is associated with altered neurodevelopment, particularly in cortices rich in cannabinoid 1 receptors and undergoing the greatest age-related thickness change in middle to late adolescence.

Barker, E. D., Ing, A., Biondo, F., Jia, T., …, Nees, F., …, & Schumann, G. (2021). Do ADHD-impulsivity and BMI have shared polygenic and neural correlates? Mol. Psychiatry, 26(3), 1019–1028. PMID:31227801, doi:10.1038/s41380-019-0444-y.

There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated ( r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) ( r = 0.17, n = 874, p = 6.5 × 10 −6 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms ( b = 0.006, 90% CIs = 0.001, 0.019) and BMI ( b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI ( b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms ( b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.

Beier, F., Löffler, M., Nees, F., Hausner, L., …, & Flor, H. (2021). Promoting neuroplasticity and neuropsychological functioning in frailty through an app-based sensorimotor training: study protocol for a randomized trial. BMC Geriatrics, 21(1), 343. doi:10.1186/s12877-021-02293-9.

Biondo, F., Thunell, C. N., Xu, B., Chu, C., …, Nees, F., …, & Schumann, G. (2021). Sex differences in neural correlates of common psychopathological symptoms in early adolescence. Psychol. Med., pp. 1–11. PMID:33769238, doi:10.1017/S0033291720005140.

BACKGROUND Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence. METHODS Participants were 14 years of age and part of the IMAGEN study, a large (N = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ). RESULTS We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region (p < 0.01, Cohen's d = -0.24), bilateral anterior and mid-cingulum (p < 0.05, Cohen's d = -0.18), right cerebellum and fusiform (p < 0.05, Cohen's d = -0.20) and left frontal superior and middle gyri (p < 0.05, Cohen's d = -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls. CONCLUSIONS Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.

Böttinger, B. W., Baumeister, S., Millenet, S. K., Barker, G. J., …, & Nees, F. (2021). Orbitofrontal control of conduct problems? Evidence from healthy adolescents processing negative facial affect. European Child & Adolescent Psychiatry. PMID:33861383, doi:10.1007/s00787-021-01770-1.

Conduct problems (CP) in patients with disruptive behavior disorders have been linked to impaired prefrontal processing of negative facial affect compared to controls. However, it is unknown whether associations with prefrontal activity during affective face processing hold along the CP dimension in a healthy population sample, and how subcortical processing is affected. We measured functional brain responses during negative affective face processing in 1444 healthy adolescents [ M = 14.39 years (SD = 0.40), 51.5% female] from the European IMAGEN multicenter study. To determine the effects of CP, we applied a two-step approach: (a) testing matched subgroups of low versus high CP, extending into the clinical range [ N = 182 per group, M = 14.44 years, (SD = 0.41), 47.3% female] using analysis of variance, and (b) considering (non)linear effects along the CP dimension in the full sample and in the high CP group using multiple regression. We observed no significant cortical or subcortical effect of CP group on brain responses to negative facial affect. In the full sample, regression analyses revealed a significant linear increase of left orbitofrontal cortex (OFC) activity with increasing CP up to the clinical range. In the high CP group, a significant inverted u-shaped effect indicated that left OFC responses decreased again in individuals with high CP. Left OFC activity during negative affective processing which is increasing with CP and decreasing in the highest CP range may reflect on the importance of frontal control mechanisms that counteract the consequences of severe CP by facilitating higher social engagement and better evaluation of social content in adolescents.

Daedelow, L. S., Banaschewski, T., Berning, M., Bokde, A. L. W., …, Nees, F., …, IMAGEN Consortium, & Heinz, A. (2021). Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults? Schizophrenia research, 228, 271–279. PMID:33493775, doi:10.1016/j.schres.2021.01.002.

OBJECTIVE To assess changes in cannabis use in young adults as a function of psychotic-like experiences. METHOD Participants were initially recruited at age 14 in high schools for the longitudinal IMAGEN study. All measures presented here were assessed at follow-ups at age 19 and at age 22, respectively. Perceived stress was only assessed once at age 22. Ever users of cannabis (N = 552) gave qualitative and quantitative information on cannabis use and psychotic-like experiences using the Community Assessment of Psychic Experiences (CAPE). Of those, nearly all n = 549 reported to have experienced at least one psychotic experience of any form at age 19. RESULTS Mean cannabis use increased from age 19 to 22 and age of first use of cannabis was positively associated with a change in cannabis use between the two time points. Change in cannabis use was not significantly associated with psychotic-like experiences at age 19 or 22. In exploratory analysis, we observed a positive association between perceived stress and the experience of psychotic experiences at age 22. CONCLUSION Age of first use of cannabis influenced trajectories of young cannabis users with later onset leading to higher increase, whereas the frequency of psychotic-like experiences was not associated with a change in cannabis use. The observed association between perceived stress and psychotic-like experiences at age 22 emphasizes the importance of stress experiences in developing psychosis independent of cannabis use.

Elkrief, L., Spinney, S., Vosberg, D. E., Banaschewski, T., …, Nees, F., …, IMAGEN Consortium, & Conrod, P. (2021). Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts. Frontiers in Psychiatry, 12, 645746. PMID:33959052, doi:10.3389/fpsyt.2021.645746.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in CNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.

Filippi, I., Galinowski, A., Lemaître, H., Massot, C., …, Nees, F., …, & Martinot, J.-L. (2021). Neuroimaging evidence for structural correlates in adolescents resilient to polysubstance use: A five-year follow-up study. Eur. Neuropsychopharmacol., 49, 11–22. PMID:33770525, doi:10.1016/j.euroneuro.2021.03.001.

Early initiation of polysubstance use (PSU) is a strong predictor of subsequent addiction, however scarce individuals present resilience capacity. This neuroimaging study aimed to investigate structural correlates associated with cessation or reduction of PSU and determine the extent to which brain structural features accounted for this resilient outcome. Participants from a European community-based cohort self-reported their alcohol, tobacco and cannabis use frequency at ages 14, 16 and 19 and had neuroimaging sessions at ages 14 and 19. We included three groups in the study: the resilient-to-PSU participants showed PSU at 16 and/or 14 but no more at 19 (n = 18), the enduring polysubstance users at 19 displayed PSU continuation from 14 or 16 (n = 193) and the controls were abstinent or low drinking participants (n = 460). We conducted between-group comparisons of grey matter volumes on whole brain using voxel-based morphometry and regional fractional anisotropy using tract-based spatial statistics. Random-forests machine-learning approach generated individual-level PSU-behavior predictions based on personality and neuroimaging features. Adolescents resilient to PSU showed significant larger grey matter volumes in the bilateral cingulate gyrus compared with enduring polysubstance users and controls at ages 19 and 14 (p<0.05 corrected) but no difference in fractional anisotropy. The larger cingulate volumes and personality trait "openness to experience" were the best precursors of resilience to PSU. Early in adolescence, a larger cingulate gyrus differentiated adolescents resilient to PSU, and this feature was critical in predicting this outcome. This study encourages further research into the neurobiological bases of resilience to addictive behaviors.

Jia, T., Xie, C., Banaschewski, T., Barker, G. J., …, Nees, F., …, & Feng, J. (2021). Neural network involving medial orbitofrontal cortex and dorsal periaqueductal gray regulation in human alcohol abuse. Sci. Adv., 7(6), eabd4074. doi:10.1126/sciadv.abd4074.

Prompted by recent evidence of neural circuitry in rodent models, functional magnetic resonance imaging and functional connectivity analyses were conducted for a large adolescent population at two ages, together with alcohol abuse measures, to characterize a neural network that may underlie the onset of alcoholism. A network centered on the medial orbitofrontal cortex (mOFC), as well as including the dorsal periaqueductal gray (dPAG), central nucleus of the amygdala, and nucleus accumbens, was identified, consistent with the rodent models, with evidence of both inhibitory and excitatory coregulation by the mOFC over the dPAG. Furthermore, significant relationships were detected between raised baseline excitatory coregulation in this network and impulsivity measures, supporting a role for negative urgency in alcohol dependence.

Kandić, M., Moliadze, V., Andoh, J., Flor, H., & Nees, F. (2021). Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation. Frontiers in Neurology, 12, 1526. doi:10.3389/fneur.2021.732034.

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed.

Liao, Z., Banaschewski, T., Bokde, A. L.W., Desrivières, S., …, Nees, F., …, & Paus, T. (2021). Similarity and stability of face network across populations and throughout adolescence and adulthood. NeuroImage, 244, 118587. doi:10.1016/j.neuroimage.2021.118587.

The ability to extract cues from faces is fundamental for social animals, including humans. An individual's profile of functional connectivity across a face network can be shaped by common organizing principles, stable individual traits, and time-varying mental states. In the present study, we used data obtained with functional magnetic resonance imaging in two cohorts, IMAGEN (N = 534) and ALSPAC (N = 465), to investigate - both at group and individual levels - the consistency of the regional profile of functional connectivity across populations (IMAGEN, ALSPAC) and time (Visits 1 to 3 in IMAGEN; age 14 to 22 years). At the group level, we found a robust canonical profile of connectivity both across populations and time. At the individual level, connectivity profiles deviated from the canonical profile, and the magnitude of this deviation related to the presence of psychopathology. These findings suggest that the brain processes faces in a highly stereotypical manner, and that the deviations from this normative pattern may be related to the risk of mental illness.

Moliadze, V., Stenner, T., Matern, S., Siniatchkin, M., Nees, F., & Hartwigsen, G. (2021). Online Effects of Beta-tACS Over the Left Prefrontal Cortex on Phonological Decisions. Neuroscience, 463, 264–271. PMID:33722674, doi:10.1016/j.neuroscience.2021.03.002.

The left posterior inferior frontal gyrus in the prefrontal cortex is a key region for phonological aspects of language processing. A previous study has shown that alpha-tACS over the prefrontal cortex applied before task processing facilitated phonological decision-making and increased task-related theta power. However, it is unclear how alpha-tACS affects phonological processing when applied directly during the task. Moreover, the frequency specificity of this effect is also unclear since the majority of neurostimulation studies tested a single frequency only. The present study addressed the question whether and how 10 Hz online tACS affects phonological decisions. To this end, 24 healthy participants received tACS at 10 Hz or 16.18 Hz (control frequency) or sham stimulation over the left prefrontal cortex during task processing in three sessions. As an unexpected finding, 16.18 Hz significantly impaired task accuracy relative to sham stimulation, without affecting response speed. There was no significant difference in phonological task performance between 10 Hz and 16.18 Hz tACS or between 10 Hz and sham stimulation. Our results support the functional relevance of the left prefrontal cortex for phonological decisions and suggest that online beta-tACS may modulate language comprehension.

Nees, F., Deserno, L., Holz, N. E., Romanos, M., & Banaschewski, T. (2021). Prediction Along a Developmental Perspective in Psychiatry: How Far Might We Go? Frontiers in Systems Neuroscience, 15, 63. doi:10.3389/fnsys.2021.670404.

Most mental disorders originate in childhood, and once symptoms present, a variety of psychosocial and cognitive maladjustments may arise. Although early childhood problems are generally associated with later mental health impairments and psychopathology, pluripotent transdiagnostic trajectories may manifest. Possible predictors range from behavioral and neurobiological mechanisms, genetic predispositions, environmental and social factors, and psychopathological comorbidity. They may manifest in altered neurodevelopmental trajectories and need to be validated capitalizing on large-scale multi-modal epidemiological longitudinal cohorts. Moreover, clinical and etiological variability between patients with the same disorders represents a major obstacle to develop effective treatments. Hence, in order to achieve stratification of patient samples opening the avenue of adapting and optimizing treatment for the individual, there is a need to integrate data from multi-dimensionally phenotyped clinical cohorts and cross-validate them with epidemiological cohort data. In the present review, we discuss these aspects in the context of externalizing and internalizing disorders summarizing the current state of knowledge, obstacles, and pitfalls. Although a large number of studies have already increased our understanding on neuropsychobiological mechanisms of mental disorders, it became also clear that this knowledge might only be the tip of the Eisberg and that a large proportion still remains unknown. We discuss prediction strategies and how the integration of different factors and methods may provide useful contributions to research and at the same time may inform prevention and intervention.

Nees, F. (2021). Vorstellung des Instituts für Medizinische Psychologie und Medizinische Soziologie (IMPS) an der Universität Kiel. Psychotherapie, Psychosomatik, medizinische Psychologie, 71(9-10), 427–428. PMID:34624902, doi:10.1055/a-1532-0265.

No abstract available

Penninck, L., Ibrahim, E. C., Artiges, E., Gorgievski, V., …, Nees, F., …, & Martinot, J.-L. (2021). Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model. Frontiers in Systems Neuroscience, 15. doi:10.3389/fnsys.2021.725413.

Price, M., Albaugh, M. D., Hahn, S., Juliano, A. C., …, Nees, F., …, & Garavan, H. (2021). Examination of the association between exposure to childhood maltreatment and brain structure in young adults: a machine learning analysis. Neuropsychopharmacology. PMID:33637836, doi:10.1038/s41386-021-00987-7.

Exposure to maltreatment during childhood is associated with structural changes throughout the brain. However, the structural differences that are most strongly associated with maltreatment remain unclear given the limited number of whole-brain studies. The present study used machine learning to identify if and how brain structure distinguished young adults with and without a history of maltreatment. Young adults (ages 18-21, n = 384) completed an assessment of childhood trauma exposure and a structural MRI as part of the IMAGEN study. Elastic net regularized regression was used to identify the structural features that identified those with a history of maltreatment. A generalizable model that included 7 cortical thicknesses, 15 surface areas, and 5 subcortical volumes was identified (area under the receiver operating characteristic curve = 0.71, p < 0.001). Those with a maltreatment history had reduced surface areas and cortical thicknesses primarily in fronto-temporal regions. This group also had larger cortical thicknesses in occipital regions and surface areas in frontal regions. The results suggest childhood maltreatment is associated with multiple measures of structure throughout the brain. The use of a large sample without exposure to adulthood trauma provides further evidence for the unique contribution of childhood trauma to brain structure. The identified regions overlapped with regions associated with psychopathology in adults with maltreatment histories, which offers insights as to how these disorders manifest.

Qi, S., Schumann, G., Bustillo, J., Turner, J. A., …, Nees, F., …, & IMAGEN Consortium. (2021). Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker. Biological psychiatry. PMID:33875230, doi:10.1016/j.biopsych.2021.01.011.

BACKGROUND Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues. METHODS A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels. RESULTS Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%. CONCLUSIONS Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.

Splittgerber, M., & Nees, F. (2021). Gehirnentwicklung im Jugendalter. Jugendhilfe, 59(4).

Das Jugendalter ist der {\"{U}}bergang von der sp{\"{a}}ten Kindheit ins Erwachsenenalter – eine Entwicklung, die von vielen Kindern und Jugendlichen herbeigesehnt wird: endlich Er- wachsen! Doch Erwachsen werden ist auch nicht immer leicht. Die Jugendzeit stellt einen Menschen vor gro{\ss}e Herausforderungen. Von sozialen Ver{\"{a}}nderungen, dem Erleben starker Gef{\"{u}}hle, der Rollen- und Identit{\"{a}}tsfindung oder dem Suchen nach Neuem ist alles dabei. Zu allem {\"{U}}berfluss macht auch das Gehirn vielf{\"{a}}ltige Ver{\"{a}}nderungen durch, die mit dem Aspekt der Jugendzeit als Phase gro{\ss}er Herausforderungen zusammenzu- h{\"{a}}ngen scheinen. Durch strukturelle und funktionelle Umbauarbeiten wird unser Gehirn besser vernetzt und spezialisierter. Das Gehirn ist in dieser Zeit extrem formbar und sucht in besonderer Weise nach neuem Input, vor allem aus sozialen und emotionalen Kontexten. Die besondere Formbarkeit macht das Gehirn allerdings auch anf{\"{a}}lliger f{\"{u}}r negative Einfl{\"{u}}sse, die sich bis in das Erwachsenenalter auswirken k{\"{o}}nnen.

Toenders, Y. J., Kottaram, A., Dinga, R., Davey, C. G., …, Nees, F., …, & Schmaal, L. (2021). Predicting depression onset in young people based on clinical, cognitive, environmental and neurobiological data. Biological psychiatry. Cognitive neuroscience and neuroimaging. PMID:33753312, doi:10.1016/j.bpsc.2021.03.005.

BACKGROUND Adolescent onset of depression is associated with long-lasting negative consequences. Identifying adolescents at risk for developing depression would enable the monitoring of risk-factors and the development of early intervention strategies. Using machine learning to combine several risk factors from multiple modalities might allow prediction of depression onset at the individual level. METHODS A subsample of a multi-site longitudinal study in adolescents, the IMAGEN study, was used to predict future (subthreshold) major depressive disorder (MDD) onset in healthy adolescents. Based on 2-year and 5-year follow-up data, participants were grouped into: 1) developing an MDD diagnosis or subthreshold MDD and 2) healthy controls. Baseline measurements of 145 variables from different modalities (clinical, cognitive, environmental and structural magnetic resonance imaging [MRI]) at age 14 were used as input to penalized logistic regression (with different levels of penalization) to predict depression onset in a training dataset (N=407). The features contributing highest to the prediction were validated in an independent hold-out sample (3 independent IMAGEN sites; N=137). RESULTS The area under the receiver operating characteristics curve (AUROC) for predicting depression onset ranged between 0.70-0.72 in the training dataset. Baseline severity of depressive symptoms, female sex, neuroticism, stressful life events and surface area of the supramarginal gyrus contributed most to the predictive model and predicted onset of depression with an AUROC between 0.68-0.72 in the independent validation sample. CONCLUSIONS This study showed that depression onset in adolescents can be predicted based on a combination multimodal data of clinical, life events, personality traits, brain structure variables.

Tschorn, M., Lorenz, R. C., O'Reilly, P. F., Reichenberg, A., …, Nees, F., …, & Rapp, M. A. (2021). Differential predictors for alcohol use in adolescents as a function of familial risk. Transl. Psychiatry, 11(1), 157. doi:10.1038/s41398-021-01260-7.

Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents ( N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk ( n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk ( n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions.

Wang, H., Fan, L., Song, M., Liu, B., …, Nees, F., …, & Jiang, T. (2021). Functional Connectivity Predicts Individual Development of Inhibitory Control during Adolescence. Cerebral Cortex, 31(5), 2686–2700. PMID:33386409, doi:10.1093/cercor/bhaa383.

Derailment of inhibitory control (IC) underlies numerous psychiatric and behavioral disorders, many of which emerge during adolescence. Identifying reliable predictive biomarkers that place the adolescents at elevated risk for future IC deficits can help guide early interventions, yet the scarcity of longitudinal research has hindered the progress. Here, using a large-scale longitudinal dataset in which the same subjects performed a stop signal task during functional magnetic resonance imaging at ages 14 and 19, we tracked their IC development individually and tried to find the brain features predicting their development by constructing prediction models using 14-year-olds' functional connections within a network or between a pair of networks. The participants had distinct between-subject trajectories in their IC development. Of the candidate connections used for prediction, ventral attention-subcortical network interconnections could predict the individual development of IC and formed a prediction model that generalized to previously unseen individuals. Furthermore, we found that connectivity between these two networks was related to substance abuse problems, an IC-deficit related problematic behavior, within 5 years. Our study reveals individual differences in IC development from mid- to late-adolescence and highlights the importance of ventral attention-subcortical network interconnections in predicting future IC development and substance abuse in adolescents.

Wesarg, C., Veer, I. M., Oei, N. Y. L., Daedelow, L. S., …, Nees, F., …, IMAGEN Consortium, & Walter, H. (2021). The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting-state functional connectivity in young adults. Hum. Brain Mapp., pp. 1–13. PMID:33818852, doi:10.1002/hbm.25433.

Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early-life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion-processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting-state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE-corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.

Xie, C., Jia, T., Rolls, E. T., Robbins, T. W., …, Nees, F., …, & IMAGEN Consortium. (2021). Reward Versus Nonreward Sensitivity of the Medial Versus Lateral Orbitofrontal Cortex Relates to the Severity of Depressive Symptoms. Biological psychiatry. Cognitive neuroscience and neuroimaging, 6(3), 259–269. PMID:33221327, doi:10.1016/j.bpsc.2020.08.017.

BACKGROUND The orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms. METHODS Activations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14. RESULTS The medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003). CONCLUSIONS Activations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores.

Zhang, Y., Luo, Q., Huang, C.-C., Lo, C.-Y. Z., …, Nees, F., …, & Feng, J. (2021). The Human Brain Is Best Described as Being on a Female/Male Continuum: Evidence from a Neuroimaging Connectivity Study. Cereb. Cortex. doi:10.1093/cercor/bhaa408.

Psychological androgyny has long been associated with greater cognitive flexibility, adaptive behavior, and better mental health, but whether a similar concept can be defined using neural features remains unknown. Using the neuroimaging data from 9620 participants, we found that global functional connectivity was stronger in the male brain before middle age but became weaker after that, when compared with the female brain, after systematic testing of potentially confounding effects. We defined a brain gender continuum by estimating the likelihood of an observed functional connectivity matrix to represent a male brain. We found that participants mapped at the center of this continuum had fewer internalizing symptoms compared with those at the 2 extreme ends. These findings suggest a novel hypothesis proposing that there exists a neuroimaging concept of androgyny using the brain gender continuum, which may be associated with better mental health in a similar way to psychological androgyny.

#### 2020

Arnaud, N., Banaschewski, T., Nees, F., Bucholz, V. N., …, & Thomasius, R. (2020). Achtsamkeit in der entwicklungsorientierten Suchtprävention und -therapie: Rational, Design und Ziele des Forschungsverbundes IMAC-Mind. Prax. Kinderpsychol. Kinderpsychiatr., 69(4), 353–374. PMID:32615894, doi:10.13109/prkk.2020.69.4.353.

Mindfulness in Development-oriented Approaches to Substance Use Prevention and Therapy: Rationale, Design and Objectives of the Research Consortium IMAC-Mind Substance use disorders (SUD) are a major contributor to morbidity and mortality. They are typically initiated during adolescence and can have fatal implications for healthy development. Despite substantial scientific advances, there remains a need to prioritize research directed at reducing risks for SUD, particularly in vulnerable periods and populations from a developmental perspective. Research indicates that reward sensitivity, impulsivity, deficient self-regulation, and stress reactivity develop markedly in childhood and adolescence and play an important role in the initiation and maintenance of SUD. A growing number of research results suggest that these factors can be favorably influenced by mindfulness-based interventions and that mindfulness-based exercises can be successfully integrated into established prevention and treatment programs. In this paper we summarize the conceptual relationships between the development and maintenance of addiction disorders and mindfulness, discuss existing empirical findings with regard to childhood and adolescence, and present the aims, study designs and intervention models of the subprojects from the ongoing research network "IMAC-Mind: Improving Mental Health and Reducing Addiction in Childhood and Adolescence through Mindfulness: Mechanisms, Prevention and Treatment".

Arnaud, N., Baldus, C., Laurenz, L. J., Bröning, S., …, & IMAC-Mind Consortium. (2020). Does a mindfulness-augmented version of the German Strengthening Families Program reduce substance use in adolescents? Study protocol for a randomized controlled trial. Trials, 21(1), 114. PMID:31992356, doi:10.1186/s13063-020-4065-1.

Bayard, F., Nymberg Thunell, C., Abé, C., Almeida, R., …, Nees, F., …, & Petrovic, P. (2020). Distinct brain structure and behavior related to ADHD and conduct disorder traits. Mol. Psychiatry, 25(11), 3020–3033. doi:10.1038/s41380-018-0202-6.

Attention-Deficit/Hyperactivity Disorder (ADHD) and conduct disorder (CD) exemplify top-down dysregulation conditions that show a large comorbidity and shared genetics. At the same time, they entail two different types of symptomology involving mainly non-emotional or emotional dysregulation. Few studies have tried to separate the specific biology underlying these two dimensions. It has also been suggested that both types of conditions consist of extreme cases in the general population where the symptoms are widely distributed. Here we test whether brain structure is specifically associated to ADHD or CD symptoms in a general population of adolescents (n = 1093) being part of the IMAGEN project. Both ADHD symptoms and CD symptoms were related to similar and overlapping MRI findings of a smaller structure in prefrontal and anterior cingulate cortex. However, our regions of interest (ROI) approach indicated that gray matter volume (GMV) and surface area (SA) in dorsolateral/dorsomedial prefrontal cortex and caudal anterior cingulate cortex were negatively associated to ADHD symptoms when controlling for CD symptoms while rostral anterior cingulate cortex GMV was negatively associated to CD symptoms when controlling for ADHD symptoms. The structural findings were mirrored in performance of neuropsychological tests dependent on prefrontal and anterior cingulate regions, showing that while performance on the Stop Signal test was specifically related to the ADHD trait, delayed discounting and working memory were related to both ADHD and CD traits. These results point towards a partially domain specific and dimensional capacity in different top-down regulatory systems associated with ADHD and CD symptoms.

Boll, S., Ueltzhoeffer, K., Roth, C., Bertsch, K., …, Nees, F., …, & Herpertz, S. C. (2020). Pain-modulating effects of oxytocin in patients with chronic low back pain. Neuropharmacology, 171, 108105. PMID:32298704, doi:10.1016/j.neuropharm.2020.108105.

The neuropeptide oxytocin (OT) has been shown to play a modulatory role in nociception. However, analgesic effects of OT in chronic pain conditions remain elusive and the neural underpinnings have not yet been investigated in humans. Here, we conducted an exploratory, randomized, placebo-controlled, cross-over study to examine effects of intranasal OT in male patients suffering from chronic low back pain (CBP) versus healthy controls (HC). N = 22 participants with CBP and 22 HCs were scanned using functional magnetic resonance imaging (fMRI) while they continuously rated either spontaneously occurring back pain or acute thermal pain stimuli applied to the lower back. During heat pain processing we found that OT versus PL attenuated pain intensity ratings and increased BOLD responses in the caudate nucleus of the striatum in CBP versus HCs. Spontaneously experienced pain in contrast to heat pain was associated with activation changes in the medial frontal cortex (MFC) and the anterior cingulate cortex (ACC) as reported in previous studies. However, we did not observe OT effects on spontaneously experienced pain in CBP patients. Overall, our preliminary data may suggest that the striatum is a key structure underlying the pain-modulating effects of OT in patients with chronic pain and adds to the growing evidence linking the neuropeptide to pain modulation in humans. Further studies on neuronal OT effects in larger samples of chronic back pain patients are needed to understand probable mechanisms of OT effects in chronic pain.

Bossier, H., Roels, S. P., Seurinck, R., Banaschewski, T., …, Nees, F., …, & Moerkerke, B. (2020). The empirical replicability of task-based fMRI as a function of sample size. Neuroimage, 212, 116601. PMID:32036019, doi:10.1016/j.neuroimage.2020.116601.

Replicating results (i.e. obtaining consistent results using a new independent dataset) is an essential part of good science. As replicability has consequences for theories derived from empirical studies, it is of utmost importance to better understand the underlying mechanisms influencing it. A popular tool for non-invasive neuroimaging studies is functional magnetic resonance imaging (fMRI). While the effect of underpowered studies is well documented, the empirical assessment of the interplay between sample size and replicability of results for task-based fMRI studies remains limited. In this work, we extend existing work on this assessment in two ways. Firstly, we use a large database of 1400 subjects performing four types of tasks from the IMAGEN project to subsample a series of independent samples of increasing size. Secondly, replicability is evaluated using a multi-dimensional framework consisting of 3 different measures: (un)conditional test-retest reliability, coherence and stability. We demonstrate not only a positive effect of sample size, but also a trade-off between spatial resolution and replicability. When replicability is assessed voxelwise or when observing small areas of activation, a larger sample size than typically used in fMRI is required to replicate results. On the other hand, when focussing on clusters of voxels, we observe a higher replicability. In addition, we observe variability in the size of clusters of activation between experimental paradigms or contrasts of parameter estimates within these.

Chaarani, B., Kan, K.-J., Mackey, S., Spechler, P. A., …, Nees, F., …, & Althoff, R. R. (2020). Neural Correlates of Adolescent Irritability and Its Comorbidity With Psychiatric Disorders. J. Am. Acad. Child Adolesc. Psychiatry. doi:10.1016/j.jaac.2019.11.028.

OBJECTIVE: Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. Here, we examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2024 14-year-adolescents from five European countries. METHOD: The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), oppositional defiant disorder (ODD), and generalized anxiety (GA). Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural MRI was examined using whole brain Voxel Based Morphometry analysis and functional MRI was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models (SEM) to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses. RESULTS: Whole brain voxel wise analysis showed that adolescent irritable mood was associated with less grey matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p<0.05). SEM models suggested that part of the observed smaller GMV is exclusively driven by irritability separate from direct relationships between GA (or ADHD, MDD, ODD) and grey matter volume. CONCLUSION: This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.

Galinowski, A., Miranda, R., Lemaître, H., Artiges, E., …, Nees, F., …, & Martinot, J.-L. (2020). Heavy drinking in adolescents is associated with change in brainstem microstructure and reward sensitivity. Addict. Biol., 25(3), e12781. PMID:31328396, doi:10.1111/adb.12781.

Heavy drinker adolescents: altered brainstem microstructure.

Grasby, K. L., Jahanshad, N., Painter, J. N., Colodro-Conde, L., …, IMAGEN Consortium, & Medland, S. E. (2020). The genetic architecture of the human cerebral cortex. Science, 367(6484), eaay6690. doi:10.1126/science.aay6690.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Guldner, S., Nees, F., & McGettigan, C. (2020). Vocomotor and Social Brain Networks Work Together to Express Social Traits in Voices. Cereb. Cortex. doi:10.1093/cercor/bhaa175.

Voice modulation is important when navigating social interactions—tone of voice in a business negotiation is very different from that used to comfort an upset child. While voluntary vocal behavior relies on a cortical vocomotor network, social voice modulation may require additional social cognitive processing. Using functional magnetic resonance imaging, we investigated the neural basis for social vocal control and whether it involves an interplay of vocal control and social processing networks. Twenty-four healthy adult participants modulated their voice to express social traits along the dimensions of the social trait space (affiliation and competence) or to express body size (control for vocal flexibility). Na{\"{i}}ve listener ratings showed that vocal modulations were effective in evoking social trait ratings along the two primary dimensions of the social trait space. Whereas basic vocal modulation engaged the vocomotor network, social voice modulation specifically engaged social processing regions including the medial prefrontal cortex, superior temporal sulcus, and precuneus. Moreover, these regions showed task-relevant modulations in functional connectivity to the left inferior frontal gyrus, a core vocomotor control network area. These findings highlight the impact of the integration of vocal motor control and social information processing for socially meaningful voice modulation.

Ivanov, I., Parvaz, M. A., Velthorst, E., Shaik, R. B., …, Nees, F., …, & Stedman, A. (2020). Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study. J. Am. Acad. Child Adolesc. Psychiatry. PMID:33011213, doi:10.1016/j.jaac.2020.08.443.

OBJECTIVE It is unclear whether deviations in brain and behavioral development, that may underpin elevated substance use during adolescence, are predispositions for or are consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug na{\"{i}}ve youth to identify possible predisposing factors for substance use initiation and its possible consequences. METHOD Among 304 drug-na{\"{i}}ve adolescents at baseline (age 14) from the IMAGEN dataset, 83 stayed drug-na{\"{i}}ve, 133 used alcohol on 1-9 occasions, 42 on 10-19 occasions, 27 on 20-39 occasions, and 19 on >40 occasions at follow-up (age 16). Baseline measures included brain activation during the Monetary Incentive Delay task, whereas data at both baseline and follow-up included measures of trait impulsivity and delay discounting. RESULTS From baseline to follow-up, impulsivity decreased in the 0 and 1-9 occasions groups (p<.004), did not change in the 10-19 and 20-29 occasions groups (p>.294), and uncharacteristically increased in the >40 occasions group (p=.046). Further, blunted mOFC activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p=.008). CONCLUSIONS These results suggest that transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. Additionally, blunted activity of the mOFC during reward outcome may underscore a predisposition to the development of more severe alcohol use in adolescents. This distinction is clinically important as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.

Jia, T., Ing, A., Quinlan, E. B., Tay, N., …, Nees, F., …, & Schumann, G. (2020). Neurobehavioural characterisation and stratification of reinforcement-related behaviour. Nat. Hum. Behav., 4(5), 544–558. PMID:32313235, doi:10.1038/s41562-020-0846-5.

Reinforcement-related cognitive processes, such as reward processing, inhibitory control and social–emotional regulation are critical components of externalising and internalising behaviours. It is unclear to what extent the deficit in each of these processes contributes to individual behavioural symptoms, how their neural substrates give rise to distinct behavioural outcomes and whether neural activation profiles across different reinforcement-related processes might differentiate individual behaviours. We created a statistical framework that enabled us to directly compare functional brain activation during reward anticipation, motor inhibition and viewing emotional faces in the European IMAGEN cohort of 2,000 14-year-old adolescents. We observe significant correlations and modulation of reward anticipation and motor inhibition networks in hyperactivity, impulsivity, inattentive behaviour and conduct symptoms, and we describe neural signatures across cognitive tasks that differentiate these behaviours. We thus characterise shared and distinct functional brain activation patterns underling different externalising symptoms and identify neural stratification markers, while accounting for clinically observed comorbidity.

Judd, N., Sauce, B., Wiedenhoeft, J., Tromp, J., …, Nees, F., …, & Klingberg, T. (2020). Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment. Proc. Natl. Acad. Sci., 117(22), 12411–12418. PMID:32430323, doi:10.1073/pnas.2001228117.

Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated ( r = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.

Koenig, J., Abler, B., Agartz, I., Åkerstedt, T., …, Nees, F., …, & Quintana, D. S. (2020). Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis. Psychophysiology, p. psyp.13688. PMID:33037836, doi:10.1111/psyp.13688.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.

Kühn, S., Banaschewski, T., Bokde, A. L. W., Büchel, C., …, Nees, F., …, & Gallinat, J. (2020). Brain structure and habitat: Do the brains of our children tell us where they have been brought up? Neuroimage, 222, 117225. PMID:32800993, doi:10.1016/j.neuroimage.2020.117225.

Recently many lifestyle factors have been shown to be associated with brain structural alterations. At present we are facing increasing population shifts from rural to urban areas, which considerably change the living environments of human beings. To investigate the association between rural vs. urban upbringing and brain structure we selected 106 14-year old adolescents of whom half were exclusively raised in rural areas and the other half who exclusively lived in cities. Voxel-based morphometry revealed a group difference in left hippocampal formation (Rural > City), which was positively associated with cognitive performance in a spatial processing task. Moreover, significant group differences were observed in spatial processing (Rural > City). A mediation analysis revealed that hippocampal formation accounted for more than half of the association between upbringing and spatial processing. The results are compatible with studies reporting earlier and more intense opportunities for spatial exploration in children brought up in rural areas. The results are interesting in the light of urban planning where spaces enabling spatial exploration for children may deserve more attention.

Kühn, S., Lisofsky, N., Banaschewski, T., Barker, G. J., …, Nees, F., …, & Gallinat, J. (2020). Hierarchical associations of alcohol use disorder symptoms in late adolescence with markers during early adolescence. Addict. Behav., 100, 106130. doi:10.1016/j.addbeh.2019.106130.

High adolescent alcohol consumption is predictive for alcohol problems later in life. To tailor interventions, early identification of risk groups for adolescent alcohol consumption is important. The IMAGEN dataset was utilized to investigate predictors for problematic alcohol consumption at age 18–20 years as a function self and parental personality and drug-related measures as well as life-events and cognitive variables all assessed at age 14 years (N = 1404). For this purpose the binary partitioning algorithm ctree was used in an explorative analysis. The algorithm recursively selects significant input variables and splits the outcome variable based on these, yielding a conditional inference tree. Four significant split variables, namely Place of residence, the Disorganization subscale of the Temperament and Character Inventory, Sex, and the Sexuality subscale of the life-events questionnaire were found to distinguish between adolescents scoring high or low on the Alcohol Use Disorders Identification Test about five years later (all p < 0.001). The analyis adds to the literature on predictors of adolescent drinking problems using a large European sample. The identified split variables could easily be collected in community samples. If their validity is proven in independent samples, they could facilitate intervention studies in the field of adolescent alcohol prevention.

Kühn, S., Mascherek, A., Banaschewski, T., Bokde, A. L. W., …, Nees, F., …, & Gallinat, J. (2020). Predicting change trajectories of neuroticism from baseline brain structure using whole brain analyses and latent growth curve models in adolescents. Sci. Rep., 10(1), 1207. PMID:31988389, doi:10.1038/s41598-020-58128-x.

Adolescence is a vulnerable time for personality development. Especially neuroticism with its link to the development of psychopathology is of interest concerning influential factors. The present study exploratorily investigates neuroanatomical signatures for developmental trajectories of neuroticism based on a voxel-wise whole-brain structural equation modelling framework. In 1,814 healthy adolescents of the IMAGEN sample, the NEO-FFI was acquired at three measurement occasions across five years. Based on a partial measurement invariance second-order latent growth curve model we conducted whole-brain analyses on structural MRI data at age 14 years, predicting change in neuroticism over time. We observed that a reduced volume in the pituitary gland was associated with the slope of neuroticism over time. However, no relations with prefrontal areas emerged. Both findings are discussed against the background of possible genetic and social influences that may account for this result.

Lett, T. A., Vogel, B. O., Ripke, S., Wackerhagen, C., …, Nees, F., …, & Walter, H. (2020). Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence. Cereb. Cortex, 30(4), 2708–2719. PMID:31828294, doi:10.1093/cercor/bhz270.

Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2–94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0–21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.

Li, J., Liu, B., Banaschewski, T., Bokde, A. L. W., …, Nees, F., …, & Jiang, T. (2020). Orbitofrontal cortex volume links polygenic risk for smoking with tobacco use in healthy adolescents. Psychol. Med., pp. 1–8. doi:10.1017/S0033291720002962.

BackgroundTobacco smoking remains one of the leading causes of preventable illness and death and is heritable with complex underpinnings. Converging evidence suggests a contribution of the polygenic risk for smoking to the use of tobacco and other substances. Yet, the underlying brain mechanisms between the genetic risk and tobacco smoking remain poorly understood.MethodsGenomic, neuroimaging, and self-report data were acquired from a large cohort of adolescents from the IMAGEN study (a European multicenter study). Polygenic risk scores (PGRS) for smoking were calculated based on a genome-wide association study meta-Analysis conducted by the Tobacco and Genetics Consortium. We examined the interrelationships among the genetic risk for smoking initiation, brain structure, and the number of occasions of tobacco use.ResultsA higher smoking PGRS was significantly associated with both an increased number of occasions of tobacco use and smaller cortical volume of the right orbitofrontal cortex (OFC). Furthermore, reduced cortical volume within this cluster correlated with greater tobacco use. A subsequent path analysis suggested that the cortical volume within this cluster partially mediated the association between the genetic risk for smoking and the number of occasions of tobacco use.ConclusionsOur data provide the first evidence for the involvement of the OFC in the relationship between smoking PGRS and tobacco use. Future studies of the molecular mechanisms underlying tobacco smoking should consider the mediation effect of the related neural structure.

Luo, Q., Zhang, L., Huang, C.-C., Zheng, Y., …, Nees, F., …, & Robbins, T. W. (2020). Association between childhood trauma and risk for obesity: a putative neurocognitive developmental pathway. BMC Med., 18(1), 278. doi:10.1186/s12916-020-01743-2.
Mascarell Maričić, L., Walter, H., Rosenthal, A., Ripke, S., …, Nees, F., …, & Heinz, A. (2020). The IMAGEN study: a decade of imaging genetics in adolescents. Mol. Psychiatry, 25(11), 2648–2671. doi:10.1038/s41380-020-0822-5.

Imaging genetics offers the possibility of detecting associations between genotype and brain structure as well as function, with effect sizes potentially exceeding correlations between genotype and behavior. However, study results are often limited due to small sample sizes and methodological differences, thus reducing the reliability of findings. The IMAGEN cohort with 2000 young adolescents assessed from the age of 14 onwards tries to eliminate some of these limitations by offering a longitudinal approach and sufficient sample size for analyzing gene-environment interactions on brain structure and function. Here, we give a systematic review of IMAGEN publications since the start of the consortium. We then focus on the specific phenotype ‘drug use' to illustrate the potential of the IMAGEN approach. We describe findings with respect to frontocortical, limbic and striatal brain volume, functional activation elicited by reward anticipation, behavioral inhibition, and affective faces, and their respective associations with drug intake. In addition to describing its strengths, we also discuss limitations of the IMAGEN study. Because of the longitudinal design and related attrition, analyses are underpowered for (epi-) genome-wide approaches due to the limited sample size. Estimating the generalizability of results requires replications in independent samples. However, such densely phenotyped longitudinal studies are still rare and alternative internal cross-validation methods (e.g., leave-one out, split-half) are also warranted. In conclusion, the IMAGEN cohort is a unique, very well characterized longitudinal sample, which helped to elucidate neurobiological mechanisms involved in complex behavior and offers the possibility to further disentangle genotype × phenotype interactions.

Modabbernia, A., Reichenberg, A., Ing, A., Moser, D. A., …, Nees, F., …, & Frangou, S. (2020). Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study. Mol. Psychiatry. PMID:32444868, doi:10.1038/s41380-020-0757-x.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30–0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|$\rho$| = 0.31−0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|$\rho$| = 0.24−0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|$\rho$| = 0.10−0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

Nees, F., Ruttorf, M., Fuchs, X., Rance, M., & Beyer, N. (2020). Brain-behaviour correlates of habitual motivation in chronic back pain. Sci. Rep., 10(1), 11090. PMID:32632166, doi:10.1038/s41598-020-67386-8.

Chronic pain may sap the motivation for positive events and stimuli. This may lead to a negative behavioural cycle reducing the establishment of appetitive habitual engagement. One potential mechanism for this might be biased learning. In our experiment, chronic back pain patients and healthy controls completed an appetitive Pavlovian-instrumental transfer procedure. We examined participants behaviour and brain activity and reported pain, depression and anxiety. Patients showed reduced habitual behaviour and increased responses in the hippocampus than controls. This behavioural bias was related to motivational value and reflected in the updating of brain activity in prefrontal–striatal–limbic circuits. Moreover, this was influenced by pain symptom duration, depression and anxiety (explained variance: up to 50.7%). Together, findings identify brain-behaviour pathways for maladaptive habitual learning and motivation in chronic back pain, which helps explaining why chronic pain can be resistant to change, and where clinical characteristics are significant modulators.

Nees, F., Ruttorf, M., Fuchs, X., Rance, M., & Beyer, N. (2020). Volumetric brain correlates of approach-avoidance behavior and their relation to chronic back pain. Brain Imaging Behav., 14(5), 1758–1768. doi:10.1007/s11682-019-00110-x.

Avoiding any harm, such as painful experiences, is an important ability for our physical and mental health. This avoidance behavior might be overactive under chronic pain, and the cortical and subcortical brain volumetry, which also often changes in chronic pain states, might be a significant correlate of this behavior. In the present study, we thus investigated the association between volumetric brain differences using 3 T structural magnetic resonance imaging and pain- versus pleasure-related approach-avoidance behavior using an Approach Avoidance Task in the laboratory in chronic back pain (N = 42; mean age: 51.34 years; 23 female) and healthy individuals (N = 43; mean age: 45.21 years; 15 female). We found significant differences in hippocampal, amygdala and accumbens volumes in patients compared to controls. The patients hippocampal volume was significantly positively related to pain avoidance, the amygdala volume to positive approach, and the accumbens volume negatively to a bias to pain avoidance over positive approach. These associations were significantly moderated by pain symptom duration. Cortical structure may thus contribute to an overacting pain avoidance system in chronic back pain, and could, together with a reduction in approaching positive stimuli, be related to maladaptive choice and decision-making processes in chronic pain.

Papanastasiou, E., Mouchlianitis, E., Joyce, D. W., McGuire, P., …, Nees, F., …, & Orfanos, D. P. (2020). Examination of the neural basis of psychotic-like experiences in adolescence during processing of emotional faces. Sci. Rep., 10(1), 5164. PMID:32198484, doi:10.1038/s41598-020-62026-7.

Contemporary theories propose that dysregulation of emotional perception is involved in the aetiology of psychosis. 298 healthy adolescents were assessed at age 14- and 19-years using fMRI while performing a facial emotion task. Psychotic-like experiences (PLEs) were assessed with the CAPE-42 questionnaire at age 19. The high PLEs group at age 19 years exhibited an enhanced response in right insular cortex and decreased response in right prefrontal, right parahippocampal and left striatal regions; also, a gradient of decreasing response to emotional faces with age, from 14 to 19 years, in the right parahippocampal region and left insular cortical area. The right insula demonstrated an increasing response to emotional faces with increasing age in the low PLEs group, and a decreasing response over time in the high PLEs group. The change in parahippocampal/amygdala and insula responses during the perception of emotional faces in adolescents with high PLEs between the ages of 14 and 19 suggests a potential ‘aberrant' neurodevelopmental trajectory for critical limbic areas. Our findings emphasize the role of the frontal and limbic areas in the aetiology of psychotic symptoms, in subjects without the illness phenotype and the confounds introduced by antipsychotic medication.

Quinlan, E. B., Banaschewski, T., Barker, G. J., Bokde, A. L. W., …, Nees, F., …, & Schumann, G. (2020). Identifying biological markers for improved precision medicine in psychiatry. Mol. Psychiatry, 25(2), 243–253. PMID:31676814, doi:10.1038/s41380-019-0555-5.

Mental disorders represent an increasing personal and financial burden and yet treatment development has stagnated in recent decades. Current disease classifications do not reflect psychobiological mechanisms of psychopathology, nor the complex interplay of genetic and environmental factors, likely contributing to this stagnation. Ten years ago, the longitudinal IMAGEN study was designed to comprehensively incorporate neuroimaging, genetics, and environmental factors to investigate the neural basis of reinforcement-related behavior in normal adolescent development and psychopathology. In this article, we describe how insights into the psychobiological mechanisms of clinically relevant symptoms obtained by innovative integrative methodologies applied in IMAGEN have informed our current and future research aims. These aims include the identification of symptom groups that are based on shared psychobiological mechanisms and the development of markers that predict disease course and treatment response in clinical groups. These improvements in precision medicine will be achieved, in part, by employing novel methodological tools that refine the biological systems we target. We will also implement our approach in low- and medium-income countries to understand how distinct environmental, socioeconomic, and cultural conditions influence the development of psychopathology. Together, IMAGEN and related initiatives strive to reduce the burden of mental disorders by developing precision medicine approaches globally.

Robert, G. H., Luo, Q., Yu, T., Chu, C., …, Nees, F., …, & Schumann, G. (2020). Association of Gray Matter and Personality Development With Increased Drunkenness Frequency During Adolescence. JAMA Psychiatry, 77(4), 409. PMID:31851304, doi:10.1001/jamapsychiatry.2019.4063.

Importance: Alcohol abuse correlates with gray matter development in adolescents, but the directionality of this association remains unknown. Objective: To investigate the directionality of the association between gray matter development and increase in frequency of drunkenness among adolescents. Design, Setting, and Participants: This cohort study analyzed participants of IMAGEN, a multicenter brain imaging study of healthy adolescents in 8 European sites in Germany (Mannheim, Dresden, Berlin, and Hamburg), the United Kingdom (London and Nottingham), Ireland (Dublin), and France (Paris). Data from the second follow-up used in the present study were acquired from January 1, 2013, to December 31, 2016, and these data were analyzed from January 1, 2016, to March 31, 2018. Analyses were controlled for sex, site, socioeconomic status, family history of alcohol dependency, puberty score, negative life events, personality, cognition, and polygenic risk scores. Personality and frequency of drunkenness were assessed at age 14 years (baseline), 16 years (first follow-up), and 19 years (second follow-up). Structural brain imaging scans were acquired at baseline and second follow-up time points. Main Outcomes and Measures: Increases in drunkenness frequency were measured by latent growth modeling, a voxelwise hierarchical linear model was used to observe gray matter volume, and tensor-based morphometry was used for gray matter development. The hypotheses were formulated before the data analyses. Results: A total of 726 adolescents (mean [SD] age at baseline, 14.4 [0.38] years; 418 [58%] female) were included. The increase in drunkenness frequency was associated with accelerated gray matter atrophy in the left posterior temporal cortex (peak: t1,710 = -5.8; familywise error (FWE)-corrected P = 7.2 × 10-5; cluster: 6297 voxels; P = 2.7 × 10-5), right posterior temporal cortex (cluster: 2070 voxels; FWE-corrected P =.01), and left prefrontal cortex (peak: t1,710 = -5.2; FWE-corrected P = 2 × 10-3; cluster: 10624 voxels; P = 1.9 × 10-7). According to causal bayesian network analyses, 73% of the networks showed directionality from gray matter development to drunkenness increase as confirmed by accelerated gray matter atrophy in late bingers compared with sober controls (n = 20 vs 60; $\beta$ = 1.25; 95% CI, -2.15 to -0.46; t1,70 = 0.3; P =.004), the association of drunkenness increase with gray matter volume at age 14 years ($\beta$ = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P =.04), the association between gray matter atrophy and alcohol drinking units ($\beta$ = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P =.02) and drunkenness frequency at age 23 years ($\beta$ = -0.16; 95% CI, -0.28 to -0.03; t1,533 = -2.5; P =.01), and the linear exposure-response curve stratified by gray matter atrophy and not by increase in frequency of drunkenness. Conclusions and Relevance: This study found that gray matter development and impulsivity were associated with increased frequency of drunkenness by sex. These results suggest that neurotoxicity-related gray matter atrophy should be interpreted with caution.

Robinson, L., Zhang, Z., Jia, T., Bobou, M., …, Nees, F., …, & Desrivières, S. (2020). Association of Genetic and Phenotypic Assessments With Onset of Disordered Eating Behaviors and Comorbid Mental Health Problems Among Adolescents. JAMA Netw. Open, 3(12), e2026874. doi:10.1001/jamanetworkopen.2020.26874.
Rosero Pahi, M., Cavalli, J., Nees, F., Flor, H., & Andoh, J. (2020). Disruption of the Prefrontal Cortex Improves Implicit Contextual Memory-Guided Attention: Combined Behavioral and Electrophysiological Evidence. Cereb. Cortex, 30(1), 20–30. PMID:31062857, doi:10.1093/cercor/bhz067.

Many studies have shown that the dorsolateral prefrontal cortex (DLPFC) plays an important role in top-down cognitive control over intentional and deliberate behavior. However, recent studies have reported that DLPFC-mediated top-down control interferes with implicit forms of learning. Here we used continuous theta-burst stimulation (cTBS) combined with electroencephalography to investigate the causal role of DLPFC in implicit contextual memory-guided attention. We aimed to test whether transient disruption of the DLPFC would interfere with implicit learning performance and related electrical brain activity. We applied neuronavigation-guided cTBS to the DLPFC or to the vertex as a control region prior to the performance of an implicit contextual learning task. We found that cTBS applied over the DLPFC significantly improved performance during implicit contextual learning. We also noted that beta-band (13–19 Hz) oscillatory power was reduced at fronto-central channels about 140 to 370 ms after visual stimulus onset in cTBS DLPFC compared with cTBS vertex. Taken together, our results provide evidence that DLPFC-mediated top-down control interferes with contextual memory-guided attention and beta-band oscillatory activity.

Schneider, I., Schmitgen, M. M., Boll, S., Roth, C., Nees, F., …, & Wolf, R. C. (2020). Oxytocin modulates intrinsic neural activity in patients with chronic low back pain. Eur. J. Pain, 24(5), 945–955. PMID:32061140, doi:10.1002/ejp.1543.

Background: Modulation of pain perception by oxytocin (OXT) has attracted increased scientific and clinical interest. Neural mechanisms underlying these effects are poorly understood. In this study, we aimed to investigate the effects of intranasally applied OXT on intrinsic neural activity in patients with chronic low back pain (cLBP). Methods: Twenty-four male patients with cLBP and 23 healthy males were examined using resting-state functional magnetic resonance imaging. Participants were scanned twice and received either intranasally applied OXT (24 international units) or placebo 40 min before scanning. The fractional amplitude of low-frequency fluctuations (fALFF) was computed to investigate regionally specific effects of OXT on intrinsic neural activity. In addition a multivariate statistical data analysis strategy was employed to explore OXT-effects on functional network strength. Results: Differential effects of OXT were observed in cLBP and healthy controls. FALFF decreased in left nucleus accumbens and right thalamus in cLBP and increased in right thalamus in healthy controls after OXT application compared to placebo. OXT also induced activity changes in bilateral thalamus, left caudate nucleus and right amygdala in cLBP. OXT was associated with increased medial frontal, parietal and occipital functional network strength, though this effect was not group-specific. Regression analyses revealed significant associations between left nucleus accumbens, left caudate nucleus and right amygdala with pain-specific psychometric scores in cLBP. Conclusions: These data suggest OXT-related modulation of regional activity and neural network strength in patients with cLBP and healthy controls. In patients, distinct regions of the pain matrix may be responsive to modulation by OXT. Significance: Our data suggest significant oxytocin-related modulation of intrinsic regional activity and neural network strength in patients with chronic low back pain and healthy controls. In patients, distinct regions of the pain matrix may be responsive to modulation by oxytocin. Therapeutic effects of oxytocin for improved pain treatment need to be further investigated.

Shen, C., Luo, Q., Jia, T., Zhao, Q., …, Nees, F., …, & Sahakian, B. J. (2020). Neural Correlates of the Dual-Pathway Model for ADHD in Adolescents. Am. J. Psychiatry, 177(9), 844–854. PMID:32375536, doi:10.1176/appi.ajp.2020.19020183.

OBJECTIVE: The dual-pathway model has been proposed to explain the heterogeneity in symptoms of attention deficit hyperactivity disorder (ADHD) by two independent psychological pathways based on distinct brain circuits. The authors sought to test whether the hypothesized cognitive and motivational pathways have separable neural correlates. METHODS: In a longitudinal community-based cohort of 1,963 adolescents, the neuroanatomical correlates of ADHD were identified by a voxel-wise association analysis and then validated using an independent clinical sample (99 never-medicated patients with ADHD, 56 medicated patients with ADHD, and 267 healthy control subjects). The cognitive and motivational pathways were assessed by neuropsychological tests of working memory, intrasubject variability, stop-signal reaction time, and delay discounting. The associations were tested between the identified neuroanatomical correlates and both ADHD symptoms 2 years later and the polygenic risk score for ADHD. RESULTS: Gray matter volumes of both a prefrontal cluster and a posterior occipital cluster were negatively associated with inattention. Compared with healthy control subjects, never-medicated patients, but not medicated patients, had significantly lower gray matter volumes in these two clusters. Working memory and intrasubject variability were associated with the posterior occipital cluster, and delay discounting was independently associated with both clusters. The baseline gray matter volume of the posterior occipital cluster predicted the inattention symptoms in a 2-year follow-up and was associated with the genetic risk for ADHD. CONCLUSIONS: The dual-pathway model has both shared and separable neuroanatomical correlates, and the shared correlate in the occipital cortex has the potential to serve as an imaging trait marker of ADHD, especially the inattention symptom domain.

Siehl, S., Wicking, M., Pohlack, S. T., Winkelmann, T., …, & Nees, F. (2020). Structural white and gray matter differences in a large sample of patients with Posttraumatic Stress Disorder and a healthy and trauma-exposed control group: Diffusion tensor imaging and region-based morphometry. NeuroImage Clin., 28, 102424. doi:10.1016/j.nicl.2020.102424.

Differences in structural white and gray matter in survivors of traumatic experiences have been related to the development and maintenance of Posttraumatic Stress Disorder (PTSD). However, there are very few studies on diffusion tensor imaging and region based morphometry comparing patients with PTSD to two control groups, namely healthy individuals with or without trauma experience. It is also unknown if differences in white and gray matter are associated. In this cross-sectional study, we examined white- and gray matter differences between 44 patients with PTSD, 49 trauma control and 61 healthy control subjects. We compared the groups applying Tract-Based Spatial Statistics (TBSS) for a whole brain white matter analysis as well as region of interest analyses for white and gray matter. First, trauma control subjects in comparison to patients with PTSD and healthy control subjects showed significantly a) higher fractional anisotropy (FA) in the left corticospinal tract and inferior fronto-occipital fasciculus than patients with PTSD, b) higher FA in the left inferior fronto-occipital-, right inferior– and right superior longitudinal fasciculi, c) higher FA in the forceps minor and d) higher volume of the left and right anterior insulae. Second, we show significant correlations between the FA in the forceps minor and the gray matter volume in the left and right anterior insulae. Third, the mean FA value in the forceps minor correlated negatively with symptom severity of PTSD and depression as well as trait anxiety, whereas the gray matter volume in the left anterior insula correlated negatively with symptom severity in PTSD. Our findings underline the importance of brain structures critically involved in emotion regulation and salience mapping. While previous studies associated these processes primarily to functional and task-based differences in brain activity, we argue that morphometrical white and gray matter differences could serve as targets in neuroscientifically-informed prevention and treatment interventions for PTSD.

Spechler, P. A., Chaarani, B., Orr, C. A., Albaugh, M. D., …, Nees, F., …, & Garavan, H. (2020). Longitudinal associations between amygdala reactivity and cannabis use in a large sample of adolescents. Psychopharmacology (Berl)., 237(11), 3447–3458. doi:10.1007/s00213-020-05624-7.

Rationale: The amygdala is a key brain structure to study in relation to cannabis use as reflected by its high-density of cannabinoid receptors and functional reactivity to processes relevant to drug use. Previously, we identified a correlation between cannabis use in early adolescence and amygdala hyper-reactivity to angry faces (Spechler et al. 2015). Objectives: Here, we leveraged the longitudinal aspect of the same dataset (the IMAGEN study) to determine (1) if amygdala hyper-reactivity predicts future cannabis use and (2) if amygdala reactivity is affected by prolonged cannabis exposure during adolescence. Methods: First, linear regressions predicted the level of cannabis use by age 19 using amygdala reactivity to angry faces measured at age 14 prior to cannabis exposure in a sample of 1119 participants. Next, we evaluated the time course of amygdala functional development from age 14 to 19 for angry face processing and how it might be associated with protracted cannabis use throughout this developmental window. We compared the sample from Spechler et al. 2015, the majority of whom escalated their use over the 5-year interval, to a matched sample of non-users. Results: Right amygdala reactivity to angry faces significantly predicted cannabis use 5 years later in a dose-response fashion. Cannabis-na{\"{i}}ve adolescents demonstrated the lowest levels of amygdala reactivity. No such predictive relationship was identified for alcohol or cigarette use. Next, follow-up analyses indicated a significant group-by-time interaction for the right amygdala. Conclusions: (1) Right amygdala hyper-reactivity is predictive of future cannabis use, and (2) protracted cannabis exposure during adolescence may alter the rate of neurotypical functional development.

Xie, C., Jia, T., Rolls, E. T., Robbins, T. W., …, Nees, F., …, & Zhang, Y. (2020). Reward Versus Nonreward Sensitivity of the Medial Versus Lateral Orbitofrontal Cortex Relates to the Severity of Depressive Symptoms. Biol. Psychiatry Cogn. Neurosci. Neuroimaging. doi:10.1016/j.bpsc.2020.08.017.
Yu, T., Jia, T., Zhu, L., Desrivières, S., …, Nees, F., …, & Stedman, A. (2020). Cannabis-Associated Psychotic-like Experiences Are Mediated by Developmental Changes in the Parahippocampal Gyrus. J. Am. Acad. Child Adolesc. Psychiatry, 59(5), 642–649. PMID:31326579, doi:10.1016/j.jaac.2019.05.034.

Objective: Cannabis consumption during adolescence has been reported as a risk factor for psychotic-like experiences (PLEs) and schizophrenia. However, brain developmental processes associated with cannabis-related PLEs are still poorly described. Method: A total of 706 adolescents from the general population who were recruited by the IMAGEN consortium had structural magnetic resonance imaging scans at both 14 and 19 years of age. We used deformation-based morphometry to map voxelwise brain changes between the two time points, using the pairwise algorithm in SPM12b. We used an a priori region-of-interest approach focusing on the hippocampus/parahippocampus to perform voxelwise linear regressions. Lifetime cannabis consumption was assessed using the European School Survey Project on Alcohol and other Drugs (ESPAD), and PLEs were assessed with the Comprehensive Assessment Psychotic-like experiences (CAPE) tool. We first tested whether hippocampus/parahippocampus development was associated with PLEs. Then we formulated and tested an a priori simple mediation model in which uncus development mediates the association between lifetime cannabis consumption and PLEs. Results: We found that PLEs were associated with reduced expansion within a specific region of the right hippocampus/parahippocampus formation, the uncus (p = .002 at the cluster level, p = .018 at the peak level). The partial simple mediation model revealed a significant total effect from lifetime cannabis consumption to PLEs (b = 0.069, 95% CI = 0.04−0.1, p =2 × 10−16), as well as a small yet significant, indirect effect of right uncus development (0.004; 95% CI = 0.0004−0.01, p = .026). Conclusion: We show here that the uncus development is involved in the cerebral basis of PLEs in a population-based sample of healthy adolescents.

Zhang, Z., Robinson, L., Jia, T., Quinlan, E. B., …, Nees, F., …, & Desrivières, S. (2020). Development of Disordered Eating Behaviors and Comorbid Depressive Symptoms in Adolescence: Neural and Psychopathological Predictors. Biol. Psychiatry. doi:10.1016/j.biopsych.2020.06.003.

Background: Eating disorders are common in adolescence and are devastating and strongly comorbid with other psychiatric disorders. Yet little is known about their etiology, knowing which would aid in developing effective preventive measures. Methods: Longitudinal assessments of disordered eating behaviors (DEBs)—binge-eating, purging, and dieting—and comorbid psychopathology were measured in 1386 adolescents from the IMAGEN study. Development of DEBs and associated mental health problems was investigated by comparing participants who reported symptoms at ages 16 or 19 years, but not at age 14 years, with asymptomatic control participants. Voxel-based morphometry and psychopathological differences at age 14 were investigated to identify risk factors for the development of DEBs and associated mental health problems. Results: DEBs and depressive symptoms developed together. Emotional and behavioral problems, including symptoms of attention-deficit/hyperactivity disorder and conduct disorder, predated their development. Alterations in frontostriatal brain areas also predated the development of DEBs and depressive symptoms. Specifically, development of binge-eating was predicted by higher gray matter volumes in the right putamen/globus pallidus at age 14. Conversely, development of purging and depressive symptoms was predicted by lower volumes in the medial orbitofrontal, dorsomedial, and dorsolateral prefrontal cortices. Lower gray matter volumes in the orbitofrontal and anterior cingulate cortices mediated the relationship between attention-deficit/hyperactivity disorder and conduct disorder symptoms and future purging and depressive symptoms. Conclusions: These findings suggest that alterations in frontal brain circuits are part of the shared etiology among eating disorders, attention-deficit/hyperactivity disorder, conduct disorder, and depression and highlight the importance of a transdiagnostic approach to treating these conditions.

#### 2019

Albaugh, M. D., Hudziak, J. J., Ing, A., Chaarani, B., …, Nees, F., …, & Potter, A. S. (2019). White matter microstructure is associated with hyperactive/inattentive symptomatology and polygenic risk for attention-deficit/hyperactivity disorder in a population-based sample of adolescents. Neuropsychopharmacology, 44(9), 1597–1603. PMID:30952157, doi:10.1038/s41386-019-0383-y.

Albaugh, M. D., Hudziak, J. J., Orr, C. A., Spechler, P. A., …, Nees, F., …, & Garavan, H. (2019). Amygdalar reactivity is associated with prefrontal cortical thickness in a large population-based sample of adolescents. PLoS One, 14(5), e0216152. PMID:31048888, doi:10.1371/journal.pone.0216152.

In structural neuroimaging studies, reduced cerebral cortical thickness in orbital and ventromedial prefrontal regions is frequently interpreted as reflecting an impaired ability to downregulate neuronal activity in the amygdalae. Unfortunately, little research has been conducted in order to test this conjecture. We examine the extent to which amygdalar reactivity is associated with cortical thickness in a population-based sample of adolescents. Data were obtained from the IMAGEN study, which includes 2,223 adolescents. While undergoing functional neuroimaging, participants passively viewed video clips of a face that started from a neutral expression and progressively turned angry, or, instead, turned to a second neutral expression. Left and right amygdala ROIs were used to extract mean BOLD signal change for the angry minus neutral face contrast for all subjects. T1-weighted images were processed through the CIVET pipeline (version 2.1.0). In variable-centered analyses, local cortical thickness was regressed against amygdalar reactivity using first and second-order linear models. In a follow-up person-centered analysis, we defined a “high reactive” group of participants based on mean amygdalar BOLD signal change for the angry minus neutral face contrast. Between-group differences in cortical thickness were examined (“high reactive” versus all other participants). A significant association was revealed between the continuous measure of amygdalar reactivity and bilateral ventromedial prefrontal cortical thickness in a second-order linear model (p < 0.05, corrected). The “high reactive” group, in comparison to all other participants, possessed reduced cortical thickness in bilateral orbital and ventromedial prefrontal cortices, bilateral anterior temporal cortices, left caudal middle temporal gyrus, and the left inferior and middle frontal gyri (p < 0.05, corrected). Results are consistent with non-human primate studies, and provide empirical support for an association between reduced prefrontal cortical thickness and amygdalar reactivity. Future research will likely benefit from investigating the degree to which psychopathology qualifies relations between prefrontal cortical structure and amygdalar reactivity.

Albaugh, M. D., Ivanova, M., Chaarani, B., Orr, C. A., …, Nees, F., …, & Potter, A. S. (2019). Ventromedial Prefrontal Volume in Adolescence Predicts Hyperactive/Inattentive Symptoms in Adulthood. Cereb. Cortex, 29(5), 1866–1874. PMID:29912404, doi:10.1093/cercor/bhy066.

Youths with attention-deficit/hyperactivity disorder symptomatology often exhibit residual inattention and/or hyperactivity in adulthood; however, this is not true for all individuals. We recently reported that dimensional, multi-informant ratings of hyperactive/inattentive symptoms are associated with ventromedial prefrontal cortex (vmPFC) structure. Herein, we investigate the degree to which vmPFC structure during adolescence predicts hyperactive/inattentive symptomatology at 5-year follow-up. Structural equation modeling was used to test the extent to which adolescent vmPFC volume predicts hyperactive/inattentive symptomatology 5 years later in early adulthood. 1104 participants (M = 14.52 years, standard deviation = 0.42; 583 females) possessed hyperactive/inattentive symptom data at 5-year follow-up, as well as quality controlled neuroimaging data and complete psychometric data at baseline. Self-reports of hyperactive/inattentive symptomatology were obtained during adolescence and at 5-year follow-up using the Strengths and Difficulties Questionnaire (SDQ). At baseline and 5-year follow-up, a hyperactive/inattentive latent variable was derived from items on the SDQ. Baseline vmPFC volume predicted adult hyperactive/inattentive symptomatology (standardized coefficient = -0.274, P < 0.001) while controlling for baseline hyperactive/inattentive symptomatology. These results are the first to reveal relations between adolescent brain structure and adult hyperactive/inattentive symptomatology, and suggest that early structural development of the vmPFC may be consequential for the subsequent expression of hyperactive/inattentive symptoms.

Baker, T. E., Castellanos-Ryan, N., Schumann, G., Cattrell, A., …, Nees, F., …, & Conrod, P. J. (2019). Modulation of orbitofrontal-striatal reward activity by dopaminergic functional polymorphisms contributes to a predisposition to alcohol misuse in early adolescence. Psychol. Med., 49(5), 801–810. PMID:29909784, doi:10.1017/S0033291718001459.

Background Abnormalities in reward circuit function are considered a core feature of addiction. Yet, it is still largely unknown whether these abnormalities stem from chronic drug use, a genetic predisposition, or both.Methods In the present study, we investigated this issue using a large sample of adolescent children by applying structural equation modeling to examine the effects of several dopaminergic polymorphisms of the D1 and D2 receptor type on the reward function of the ventral striatum (VS) and orbital frontal cortex (OFC), and whether this relationship predicted the propensity to engage in early alcohol misuse behaviors at 14 years of age and again at 16 years of age.Results The results demonstrated a regional specificity with which the functional polymorphism rs686 of the D1 dopamine receptor (DRD1) gene and Taq1A of the ANKK1 gene influenced medial and lateral OFC activation during reward anticipation, respectively. Importantly, our path model revealed a significant indirect relationship between the rs686 of the DRD1 gene and early onset of alcohol misuse through a medial OFC × VS interaction.Conclusions These findings highlight the role of D1 and D2 in adjusting reward-related activations within the mesocorticolimbic circuitry, as well as in the susceptibility to early onset of alcohol misuse.

Barker, E. D., Ing, A., Biondo, F., Jia, T., …, Nees, F., …, & Schumann, G. (2019). Do ADHD-impulsivity and BMI have shared polygenic and neural correlates? Mol. Psychiatry. doi:10.1038/s41380-019-0444-y.

There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r = 0.17, n = 874, p = 6.5 × 10−6 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b = 0.006, 90% CIs = 0.001, 0.019) and BMI (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.

Bartholdy, S., O'Daly, O. G., Campbell, I. C., Banaschewski, T., …, Nees, F., …, & Stedman, A. (2019). Neural Correlates of Failed Inhibitory Control as an Early Marker of Disordered Eating in Adolescents. Biol. Psychiatry, 85(11), 956–965. PMID:31122340, doi:10.1016/j.biopsych.2019.01.027.

Background: Binge eating and other forms of disordered eating behavior (DEB)are associated with failed inhibitory control. This study investigated the neural correlates of failed inhibitory control as a potential biomarker for DEB. Methods: The study used prospective longitudinal data from the European IMAGEN study adolescent cohort. Participants completed baseline assessments (questionnaires and a brain scan [functional magnetic resonance imaging])at 14 years of age and a follow-up assessment (questionnaires)at 16 years of age. Self-reported binge eating and/or purging were used to indicate presence of DEB. Neural correlates of failed inhibition were assessed using the stop signal task. Participants were categorized as healthy control subjects (reported no DEB at both time points), maintainers (reported DEB at both time points), recoverers (reported DEB at baseline only), and developers (reported DEB at follow-up only). Forty-three individuals per group with complete scanning data were matched on gender, age, puberty, and intelligence (N = 172). Results: At baseline, despite similar task performance, incorrectly responding to stop signals (failed inhibitory control)was associated with greater recruitment of the medial prefrontal cortex and anterior cingulate cortex in the developers compared with healthy control subjects and recoverers. Conclusions: Greater recruitment of the medial prefrontal and anterior cingulate regions during failed inhibition accords with abnormal evaluation of errors contributing to DEB development. As this precedes symptom onset and is evident despite normal task performance, neural responses during failed inhibition may be a useful biomarker of vulnerability for DEB. This study highlights the potential value of prospective neuroimaging studies for identifying markers of illness before the emergence of behavior changes.

Brislin, S. J., Patrick, C. J., Flor, H., Nees, F., …, & Foell, J. (2019). Extending the Construct Network of Trait Disinhibition to the Neuroimaging Domain: Validation of a Bridging Scale for Use in the European IMAGEN Project. Assessment, 26(4), 567–581. PMID:29557190, doi:10.1177/1073191118759748.

Trait disinhibition, a clinical-liability construct, has well-established correlates in the diagnostic, self-rating, task-behavioral, and brain potential response domains. Recently, studies have begun to test for neuroimaging correlates of this liability factor, but more work of this type using larger data sets is needed to clarify its brain bases. The current study details the development and validation of a scale measure of trait disinhibition composed of questionnaire items available in the IMAGEN project, a large-scale longitudinal study of factors contributing to substance abuse that includes clinical interview, self-report personality, task-behavioral, neuroimaging, and genomic measures. Using a construct-rating and psychometric refinement approach, a scale was developed that evidenced: (a) positive relations with interview-assessed psychopathology in the IMAGEN sample, both concurrently and prospectively and (b) positive associations with scale measures of disinhibition and reported psychopathology, and a robust negative correlation with P3 brain response, in a separate adult sample (M age = 19.5). These findings demonstrate that a common scale measure can index this construct from adolescence through to early adulthood, and set the stage for systematic work directed at identifying neural and genetic biomarkers of this key liability construct using existing and future data from the IMAGEN project.

Cao, Z., Bennett, M., Orr, C. A., Icke, I., …, Nees, F., …, & Whelan, R. (2019). Mapping adolescent reward anticipation, receipt, and prediction error during the monetary incentive delay task. Hum. Brain Mapp., 40(1), 262–283. PMID:30240509, doi:10.1002/hbm.24370.

The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental period's association with altered reward sensitivity. Here, a large sample (n = 1,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward-related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.

Chaarani, B., Kan, K.-J., Mackey, S., Spechler, P. A., …, Nees, F., …, & Tahmasebi, A. M. (2019). Low Smoking Exposure, the Adolescent Brain, and the Modulating Role of CHRNA5 Polymorphisms. Biol. Psychiatry Cogn. Neurosci. Neuroimaging, 4(7), 672–679. PMID:31072760, doi:10.1016/j.bpsc.2019.02.006.

Ernst, M., Benson, B., Artiges, E., Gorka, A. X., …, Nees, F., …, & Martinot, J.-L. (2019). Pubertal maturation and sex effects on the default-mode network connectivity implicated in mood dysregulation. Transl. Psychiatry, 9(1), 103. PMID:30804326, doi:10.1038/s41398-019-0433-6.

This study examines the effects of puberty and sex on the intrinsic functional connectivity (iFC) of brain networks, with a focus on the default-mode network (DMN). Consistently implicated in depressive disorders, the DMN's function may interact with puberty and sex in the development of these disorders, whose onsets peak in adolescence, and which show strong sex disproportionality (females > males). The main question concerns how the DMN evolves with puberty as a function of sex. These effects are expected to involve within- and between-network iFC, particularly, the salience and the central-executive networks, consistent with the Triple-Network Model. Resting-state scans of an adolescent community sample (n = 304, male/female: 157/147; mean/std age: 14.6/0.41 years), from the IMAGEN database, were analyzed using the AFNI software suite and a data reduction strategy for the effects of puberty and sex. Three midline regions (medial prefrontal, pregenual anterior cingulate, and posterior cingulate), within the DMN and consistently implicated in mood disorders, were selected as seeds. Within- and between-network clusters of the DMN iFC changed with pubertal maturation differently in boys and girls (puberty-X-sex). Specifically, pubertal maturation predicted weaker iFC in girls and stronger iFC in boys. Finally, iFC was stronger in boys than girls independently of puberty. Brain–behavior associations indicated that lower connectivity of the anterior cingulate seed predicted higher internalizing symptoms at 2-year follow-up. In conclusion, weaker iFC of the anterior DMN may signal disconnections among circuits supporting mood regulation, conferring risk for internalizing disorders.

Griebe, M., Ebert, A., Nees, F., Katic, K., …, & Szabo, K. (2019). Enhanced cortisol secretion in acute transient global amnesia. Psychoneuroendocrinology, 99, 72–79. PMID:30193207, doi:10.1016/j.psyneuen.2018.08.033.

Introduction: Stress-related transient inhibition of memory formation in the hippocampus has been hypothesized as one of the underlying pathomechanisms of transient global amnesia (TGA). TGA episodes, during which patients cannot encode and recall new information (anterograde amnesia affecting episodic long-term memory), are frequently preceded by a psychologically or physically stressful event. Methods: We measured salivary cortisol during acute TGA in 14 patients, as well as cortisol day-profiles and the effect of experimental exposure to stress (using the socially evaluated cold pressor test) on cortisol levels during the subacute phase. We assessed psychiatric comorbidity as well as depression, trait anxiety and chronic stress. These findings were compared with data of 20 healthy controls. Findings: Nine patients reported a precipitating stressor and all 14 developed typical hippocampal lesions on follow-up MRI. During TGA, salivary cortisol levels were more than 3-fold higher compared to time-matched day levels. While there was no difference in mean cortisol levels of the diurnal rhythm, we found a significant interaction between groups during experimental stress exposure (p = 0.049) with the TGA group revealing a higher cortisol increase. The TGA group reported higher levels of depressive symptomatology (CES-D) and higher scores of chronic stress (TICS) compared with the control group and there was a significant correlation between cortisol increase during TGA and the results of self-rating according to the CES-D (r = 0.615; p = 0.004), as well as to the STAI (r = 0.702; p = 0.001). Conclusion: Our findings of enhanced secretion of cortisol in acute TGA patients correlating with symptoms of depression and anxiety and a persisting hyperreactivity to experimental stress in the subacute phase support the hypothesis that stress might be significant for the pathogenesis of TGA.

Haaker, J., Maren, S., Andreatta, M., Merz, C. J., …, Nees, F., …, & Lonsdorf, T. B. (2019). Making translation work: Harmonizing cross-species methodology in the behavioural neuroscience of Pavlovian fear conditioning. Neurosci. Biobehav. Rev., 107, 329–345. PMID:31521698, doi:10.1016/j.neubiorev.2019.09.020.

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.

Ing, A., Sämann, P. G., Chu, C., Tay, N., …, Nees, F., …, & Schumann, G. (2019). Identification of neurobehavioural symptom groups based on shared brain mechanisms. Nat. Hum. Behav., 3(12), 1306–1318. PMID:31591521, doi:10.1038/s41562-019-0738-8.

Most psychopathological disorders develop in adolescence. The biological basis for this development is poorly understood. To enhance diagnostic characterization and develop improved targeted interventions, it is critical to identify behavioural symptom groups that share neural substrates. We ran analyses to find relationships between behavioural symptoms and neuroimaging measures of brain structure and function in adolescence. We found two symptom groups, consisting of anxiety/depression and executive dysfunction symptoms, respectively, that correlated with distinct sets of brain regions and inter-regional connections, measured by structural and functional neuroimaging modalities. We found that the neural correlates of these symptom groups were present before behavioural symptoms had developed. These neural correlates showed case–control differences in corresponding psychiatric disorders, depression and attention deficit hyperactivity disorder in independent clinical samples. By characterizing behavioural symptom groups based on shared neural mechanisms, our results provide a framework for developing a classification system for psychiatric illness that is based on quantitative neurobehavioural measures.

Jia, T., Chu, C., Liu, Y., van Dongen, J., …, Nees, F., …, & Desrivières, S. (2019). Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group. Mol. Psychiatry. PMID:31811260, doi:10.1038/s41380-019-0605-z.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Kühn, S., Mascharek, A., Banaschewski, T., Bodke, A., …, Nees, F., …, & Gallinat, J. (2019). Predicting development of adolescent drinking behaviour from whole brain structure at 14 years of age. Elife, 8. PMID:31262402, doi:10.7554/eLife.44056.

Adolescence is a common time for initiation of alcohol use and development of alcohol use disorders. The present study investigates neuroanatomical predictors for trajectories of future alcohol use based on a novel voxel-wise whole-brain structural equation modeling framework. In 1814 healthy adolescents of the IMAGEN sample, the Alcohol Use Disorder Identification Test (AUDIT) was acquired at three measurement occasions across five years. Based on a two-part latent growth curve model, we conducted whole-brain analyses on structural MRI data at age 14, predicting change in alcohol use score over time. Higher grey-matter volumes in the caudate nucleus and the left cerebellum at age 14 years were predictive of stronger increase in alcohol use score over 5 years. The study is the first to demonstrate the feasibility of running separate voxel-wise structural equation models thereby opening new avenues for data analysis in brain imaging.

Löffler, M., Schneider, P., Schuh-Hofer, S., Kamping, S., …, Nees, F.*, & Flor, H.*. (2019). Stress-induced analgesia in patients with chronic musculoskeletal pain and healthy controls. preprint. arXiv:1902.07795.

Introduction: Individuals with chronic musculoskeletal pain show impairments in their pain-modulatory capacity. Stress-induced analgesia (SIA) is a paradigm of endogenous pain inhibition mainly tested in animals. It has not been tested in patients with chronic pain despite the important role of stress in pain modulation and the chronicity process. Methods: SIA was tested in 22 patients with chronic musculoskeletal pain and 18 healthy participants matched for age and gender. Pain thresholds, pain tolerance and suprathreshold pain sensitivity were examined before and after a cognitive stressor. Additionally, chronic stress levels, pain catastrophizing and pain characteristics were assessed as potential modulating factors. Results: Patients with chronic musculoskeletal pain compared to healthy controls showed significantly impaired SIA (F(1,37)=5.63, p=.02) for pain thresholds, but not pain tolerance (F(1,37)=0.05, p=.83) and stress-induced hyperalgesia (SIH) to suprathreshold pain ratings (F(1,37)=7.76, p=.008). Patients (r(22)=-0.50, p=.05) but not controls (r(18)=-0.39, p=.13) with high catastrophizing had low SIA as assessed by pain thresholds. In controls suprathreshold pain ratings were significantly positively correlated with catastrophizing (r(18)=0.57, p=.03) and life-time stress exposure (r(18)=0.54, p=.03). In patients neither catastrophizing (r(22)=0.21, p=.34) nor stress exposure (r(22)=0.34, p=.34) were associated with suprathreshold SIH. Discussion: Our data suggest impairments of SIA and SIH in patients with chronic musculoskeletal pain. Catastrophizing was associated with deficient SIA in the patients and higher pain ratings in controls. High life time stress also increased pain ratings in the controls.

Luo, Q., Chen, Q., Wang, W., Desrivières, S., …, Nees, F., …, & Feng, J. (2019). Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents. JAMA Psychiatry, 76(4), 435. PMID:30649180, doi:10.1001/jamapsychiatry.2018.4126.

Importance: Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology. Objective: To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations. Design, Setting, and Participants: Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018. Main Outcomes and Measures: Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip. Results: The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in SLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10-18; and 4.44% in the right hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10-19) and also with a lower gene expression of SLC39A8 specifically in the putamen (t127 = -3.87; P = 1.70 × 10-4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = -3.05; P =.002; n = 157) and unaffected siblings (z = -2.08; P =.04; n = 149). Conclusions and Relevance: Our results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation..

Meng, W., Sjöholm, L. K., Kononenko, O., Tay, N., …, IMAGEN Consortium, & Liu, Y. (2019). Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence. Mol. Psychiatry. doi:10.1038/s41380-019-0588-9.

Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.

Müller, C. P., Chu, C., Qin, L., Liu, C., …, Nees, F., …, & Schumann, G. (2019). The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking: A Translational Study. Cereb. Cortex, 29(4), 1736–1751. PMID:30721969, doi:10.1093/cercor/bhy341.

Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-$\kappa$B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 × 10?19) and regional methylation (P = 5.90 × 10-25). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-$\kappa$B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.

Nees, F., Usai, K., Löffler, M., & Flor, H. (2019). The evaluation and brain representation of pleasant touch in chronic and subacute back pain. Neurobiol. Pain, 5(September 2018), 100025. doi:10.1016/j.ynpai.2018.10.002.

If touch is perceived as pleasant, it can counteract the experience of pain. However, its pain-inhibitory function might be disturbed in chronic pain and this could contribute to pain-related interference. We investigated the perception of pleasant touch and its brain correlates in chronic back pain patients (CBP) compared to subacute back pain patients (SABP) and healthy controls (HC) using soft brush strokes. CBP showed less positive evaluations of touch. We found the highest activation in somatosensory and insular cortices in CBP, ventral striatum (VS) in SABP, and the orbitofrontal cortex in HC. Brain responses were significantly positively correlated with pleasantness ratings in HC and SABP, but not CBP. Further, the insula responses in CBP were positively correlated with pain-related interference and the VS activation in SABP correlated negatively with affective distress. Brain and behavioral changes in the processing of touch and its pleasantness may be a marker of pain chronicity and raise questions about the therapeutic value of pleasant touch in pain prevention and treatment.

Nees, F., Löffler, M., Usai, K., & Flor, H. (2019). Hypothalamic-pituitary-adrenal axis feedback sensitivity in different states of back pain. Psychoneuroendocrinology, 101, 60–66. PMID:30414593, doi:10.1016/j.psyneuen.2018.10.026.

Pain normally signals a threat to bodily integrity and causes emotional distress. Acute pain serves a protective function, yet, when pain turns chronic, the protective function is lost. A chain of psychophysiological alterations including changes in the stress regulation system, apparent in dysfunctional activity and responsivity of the hypothalamic-pituitary-adrenal (HPA) axis, might be an important factor in this context. Moreover, maladaptive responses may be complicated by affective comorbid symptoms such as anxiety and depression, and alter nociceptive processing. However, the relationship among pain chronicity, stress regulation, and contributing components of comorbid symptomatology as well as somatosensory profiles has rarely been examined. In the present study, we obtained diurnal cortisol profiles at baseline and feedback regulation (following a dexamethasone suppression test (DST)) in subacute (SABP) and chronic (CBP) back pain patients and healthy control individuals (HC). We also assessed anxiety, depression and chronic stress levels and used quantitative sensory testing (QST) to detect sensory abnormalities. We found a hyper-suppression of cortisol following DST and thus enhanced negative stress feedback sensitivity in SABP compared to both CBP and HC. In SABP, DST-related cortisol levels were negatively associated with pain intensity, mediated by cold pain thresholds and anxiety. These data support a stress model of pain chronicity and suggest that stress responses might be indicators of individual vulnerability in the transition period of subacute pain.

Nees, F., Pohlack, S. T., Grimm, O., Winkelmann, T., Zidda, F.*, & Flor, H.*. (2019). White matter correlates of contextual pavlovian fear extinction and the role of anxiety in healthy humans. Cortex, 121, 179–188. PMID:31629196, doi:10.1016/j.cortex.2019.08.020.

Pavlovian contextual fear extinction is viewed as an important mechanism for behavioral adaptation in everyday life, including challenging situations of stress and anxiety. It has frequently been shown to relate to the function of brain areas like the hippocampus and medial prefrontal cortex (mPFC), while the role of structural properties, like white matter tracts in these regions, has been less studied. We employed diffusion tensor imaging to determine structural white matter connectivity (cingulum and uncinate fasciculus) correlates of contextual pavlovian fear extinction indicators measured through functional magnetic resonance imaging, skin conductance responses (SCRs) and self-reports of valence, arousal and contingency in 93 healthy individuals. Higher fractional anisotropy values in the hippocampal cingulum were significantly related to higher SCRs during extinction of contextual conditioned responses (explained variance: 11.2%) as an indicator of extinction deficits on the level of physiological arousal. However, FA was neither related to any of the other fear extinction measures, nor did we find associations with functional extinction responses in the hippocampus or mPFC. Trait anxiety was a significant moderator of the SCR-hippocampal cingulum association (explained variance: 32.09%). The data add evidence for a critical role of the hippocampal formation in contextual pavlovian extinction, and, together with the strong effect of trait anxiety, may have implications for the development of anxiety disorders where contextual extinction learning deficits are observed.

Orr, C. A., Spechler, P. A., Cao, Z., Albaugh, M. D., …, Nees, F., …, & Garavan, H. (2019). Grey matter volume differences associated with extremely low levels of cannabis use in adolescence. J. Neurosci., 39(10), 1817–1827. PMID:30643026, doi:10.1523/JNEUROSCI.3375-17.2018.

Rates of cannabis use among adolescents are high, and are increasing concurrent with changes in the legal status of marijuana and societal attitudes regarding its use. Recreational cannabis use is understudied, especially in the adolescent period when neural maturation may make users particularly vulnerable to the effects of $\Delta$-9-tetrahydrocannabinol (THC) on brain structure. In the current study, we used voxel-based morphometry to compare gray matter volume (GMV) in forty-six 14-year-old human adolescents (males and females) with just one or two instances of cannabis use and carefully matched THC-naive controls. We identified extensive regions in the bilateral medial temporal lobes as well as the bilateral posterior cingulate, lingual gyri, and cerebellum that showed greater GMV in the cannabis users. Analysis of longitudinal data confirmed that GMV differences were unlikely to precede cannabis use. GMV in the temporal regions was associated with contemporaneous performance on the Perceptual Reasoning Index and with future generalized anxiety symptoms in the cannabis users. The distribution of GMV effects mapped onto biomarkers of the endogenous cannabinoid system providing insight into possible mechanisms for these effects.

Rosero, M. A., Winkelmann, T., Pohlack, S. T., Cavalli, J., Nees, F.*, & Flor, H.*. (2019). Memory-guided attention: bilateral hippocampal volume positively predicts implicit contextual learning. Brain Struct. Funct., 224(6), 1999–2008. PMID:31104120, doi:10.1007/s00429-019-01887-9.

Several studies have begun to demonstrate that contextual memories constitute an important mechanism to guide our attention. Although there is general consensus that the hippocampus is involved in the encoding of contextual memories, it is controversial whether this structure can support implicit forms of contextual memory. Here, we combine automated segmentation of structural MRI with neurobehavioral assessment of implicit contextual memory-guided attention to test the hypothesis that hippocampal volume would predict the magnitude of implicit contextual learning. Forty healthy subjects underwent 3T magnetic resonance imaging brain scanning with subsequent automatic measurement of the total brain and hippocampal (right and left) volumes. Implicit learning of contextual information was measured using the contextual cueing task. We found that both left and right hippocampal volumes positively predicted the magnitude of implicit contextual learning. Larger hippocampal volume was associated with superior implicit contextual memory performance. This study provides compelling evidence that implicit contextual memory-guided attention is hippocampus-dependent.

Ruan, H., Zhou, Y., Luo, Q., Robert, G. H., …, Nees, F., …, & Feng, J. (2019). Adolescent binge drinking disrupts normal trajectories of brain functional organization and personality maturation. NeuroImage Clin., 22, 101804. PMID:30991616, doi:10.1016/j.nicl.2019.101804.

Adolescent binge drinking has been associated with higher risks for the development of many health problems throughout the lifespan. Adolescents undergo multiple changes that involve the co-development processes of brain, personality and behavior; therefore, certain behavior, such as alcohol consumption, can have disruptive effects on both brain development and personality maturation. However, these effects remain unclear due to the scarcity of longitudinal studies. In the current study, we used multivariate approaches to explore discriminative features in brain functional architecture, personality traits, and genetic variants in 19-year-old individuals (n = 212). Taking advantage of a longitudinal design, we selected features that were more drastically altered in drinkers with an earlier onset of binge drinking. With the selected features, we trained a hierarchical model of support vector machines using a training sample (n = 139). Using an independent sample (n = 73), we tested the model and achieved a classification accuracy of 71.2%. We demonstrated longitudinally that after the onset of binge drinking the developmental trajectory of improvement in impulsivity slowed down. This study identified the disrupting effects of adolescent binge drinking on the developmental trajectories of both brain and personality.

Seo, S., Beck, A., Matthis, C., Genauck, A., …, Nees, F., …, & Obermayer, K. (2019). Risk profiles for heavy drinking in adolescence: differential effects of gender. Addict. Biol., 24(4), 787–801. PMID:29847018, doi:10.1111/adb.12636.

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi-domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross-sectional analyses on the large IMAGEN sample (N ≈ 1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19—for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19-year-olds' bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

Spechler, P. A., Chaarani, B., Orr, C. A., Mackey, S., …, Nees, F., …, & Mennigen, E. (2019). Neuroimaging Evidence for Right Orbitofrontal Cortex Differences in Adolescents With Emotional and Behavioral Dysregulation. J. Am. Acad. Child Adolesc. Psychiatry, 58(11), 1092–1103. PMID:31004740, doi:10.1016/j.jaac.2019.01.021.

Objective: To characterize the structural and functional neurobiology of a large group of adolescents exhibiting a behaviorally and emotionally dysregulated phenotype. Method: Adolescents aged 14 years from the IMAGEN study were investigated. Latent class analysis (LCA) on the Strengths and Difficulties Questionnaire (SDQ) was used to identify a class of individuals with elevated behavioral and emotional difficulties (“dysregulated”; n = 233) who were compared to a matched sample from a low symptom class (controls, n = 233). Whole-brain gray matter volume (GMV) images were compared using a general linear model with 10,000 random label permutations. Regional GMV findings were then probed for functional differences from three functional magnetic resonance imaging (fMRI) tasks. Significant brain features then informed mediation path models linking the likelihood of psychiatric disorders (DSM-IV) with dysregulation. Results: Whole-brain differences were found in the right orbitofrontal cortex (R.OFC; p < .05; k = 48), with dysregulated individuals exhibiting lower GMV. The dysregulated group also exhibited higher activity in this region during successful inhibitory control (F1,429 = 7.53, p < .05). Path analyses indicated significant direct effects between the likelihood of psychopathologies and dysregulation. Modeling the R.OFC as a mediator returned modest partial effects, suggesting that the path linking the likelihood of an anxiety or conduct disorder diagnoses to dysregulation is partially explained by this anatomical feature. Conclusion: A large sample of dysregulated adolescents exhibited lower GMV in the R.OFC relative to controls. Dysregulated individuals also exhibited higher regional activations when exercising inhibitory control at performance levels comparable to those of controls. These findings suggest a neurobiological marker of dysregulation and highlight the role of the R.OFC in impaired emotional and behavioral control.

Spechler, P. A., Allgaier, N., Chaarani, B., Whelan, R., …, Nees, F., …, & Tahmasebi, A. M. (2019). The initiation of cannabis use in adolescence is predicted by sex‐specific psychosocial and neurobiological features. Eur. J. Neurosci., 50(3), 2346–2356. PMID:29889330, doi:10.1111/ejn.13989.

Cannabis use initiated during adolescence might precipitate negative consequences in adulthood. Thus, predicting adolescent cannabis use prior to any exposure will inform the aetiology of substance abuse by disentangling predictors from consequences of use. In this prediction study, data were drawn from the IMAGEN sample, a longitudinal study of adolescence. All selected participants (n = 1,581) were cannabis-na{\"{i}}ve at age 14. Those reporting any cannabis use (out of six ordinal use levels) by age 16 were included in the outcome group (N = 365, males n = 207). Cannabis-na{\"{i}}ve participants at age 14 and 16 were included in the comparison group (N = 1,216, males n = 538). Psychosocial, brain and genetic features were measured at age 14 prior to any exposure. Cross-validated regularized logistic regressions for each use level by sex were used to perform feature selection and obtain prediction error statistics on independent observations. Predictors were probed for sex- and drug-specificity using post-hoc logistic regressions. Models reliably predicted use as indicated by satisfactory prediction error statistics, and contained psychosocial features common to both sexes. However, males and females exhibited distinct brain predictors that failed to predict use in the opposite sex or predict binge drinking in independent samples of same-sex participants. Collapsed across sex, genetic variation on catecholamine and opioid receptors marginally predicted use. Using machine learning techniques applied to a large multimodal dataset, we identified a risk profile containing psychosocial and sex-specific brain prognostic markers, which were likely to precede and influence cannabis initiation.

Tay, N., Macare, C., Liu, Y., Ruggeri, B., …, Nees, F., …, & Schumann, G. (2019). Allele-specific methylation of SpDEF: A novel moderator of psychosocial stress and substance abuse. Am. J. Psychiatry, 176(2), 146–155. PMID:30525907, doi:10.1176/appi.ajp.2018.17121360.

Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population. Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study. Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use. Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

Wahl, A.-S.*, Löffler, M.*, Hausner, L., Ruttorf, M., Nees, F., & Frölich, L. (2019). Case report: a giant arachnoid cyst masking Alzheimer's disease. BMC Psychiatry, 19(1), 274. PMID:31488095, doi:10.1186/s12888-019-2247-8.

BACKGROUND: Intracranial arachnoid cysts are usually benign congenital findings of neuroimaging modalities, sometimes however, leading to focal neurological and psychiatric comorbidities. Whether primarily clinically silent cysts may become causally involved in cognitive decline in old age is neither well examined nor understood. CASE PRESENTATION: A 66-year old caucasian man presenting with a giant left-hemispheric frontotemporal cyst without progression of size, presented with slowly progressive cognitive decline. Neuropsychological assessment revealed an amnestic mild cognitive impairment (MCI) without further neurological or psychiatric symptoms. The patient showed mild medio-temporal lobe atrophy on structural MRI. Diffusion tensor and functional magnetic resonance imaging depicted a rather sustained function of the strongly suppressed left hemisphere. Amyloid-PET imaging was positive for increased amyloid burden and he was homozygous for the APOE$\epsilon$3-gene. A diagnosis of MCI due to Alzheimer's disease was given and a co-morbidity with a silent arachnoid cyst was assumed. To investigate, if a potentially reduced CSF flow due to the giant arachnoid cyst contributed to the early manifestation of AD, we reviewed 15 case series of subjects with frontotemporal arachnoid cysts and cognitive decline. However, no increased manifestation of neurodegenerative disorders was reported. CONCLUSIONS: With this case report, we illustrate the necessity of a systematic work-up for neurodegenerative disorders in patients with arachnoid cysts and emerging cognitive decline. We finally propose a modus operandi for the stratification and management of patients with arachnoid cysts potentially susceptive for cognitive dysfunction.

Zidda, F.*, Griebe, M.*, Ebert, A., Ruttorf, M., …, Nees, F.*, & Szabo, K.*. (2019). Resting-state connectivity alterations during transient global amnesia. NeuroImage Clin., 23(May), 101869. PMID:31153000, doi:10.1016/j.nicl.2019.101869.

While the pathophysiology of transient global amnesia (TGA)is not understood, due to the specific nature of the clinical deficits, transient dysfunction in the medial temporal lobe, especially in the hippocampus, is assumed; however, concomitant disturbances in other brain regions and in executive function have been postulated. In this study, a cohort of 16 patients was prospectively recruited from the emergency department for resting-state functional MRI (fMRI)during the acute stage of TGA, as confirmed by a standardized neuropsychological assessment. Twenty age- and sex-matched controls, as well as twenty patients with a history of TGA, were recruited for comparison. Functional data were processed using independent component analysis (ICA), allowing the complete automatic (data-driven)identification of spontaneous network dynamics. We documented a severe disturbance in anterograde episodic long-term memory in all patients. Group-based ICA of resting-state data in acute TGA patients versus that of controls and patients with a past TGA episode demonstrated reduced FC mainly of structures belonging to the executive network (EN), but also the hippocampus, confirming its pathophysiological involvement in the disorder, as well as areas belonging to the salience network and other subcortical regions. No significant differences were found when comparing connectivity in patients with a history of TGA and controls. Our findings strengthen previous empirical and theoretical accounts of hippocampal and executive dysfunction in TGA. The disruption of frontal, parietal and insular control regions, together with disruption in the hippocampus, provides a new interpretation for the pathophysiology and neuropsychological profile of this neurological disorder on a large-scale network level

#### 2018

Becker, S., Navratilova, E., Nees, F., & Van Damme, S. (2018). Shared Mechanisms of Chronic Pain and Emotional-Motivational Problems: From Basic Science to the Clinics. Pain Res. Manag. (pp. 1–2). PMID:30581516, doi:10.1155/2018/9305026.
Becker, S., Navratilova, E., Nees, F., & Van Damme, S. (2018). Emotional and Motivational Pain Processing: Current State of Knowledge and Perspectives in Translational Research. Pain Res. Manag., 2018, 1–12. PMID:30123398, doi:10.1155/2018/5457870.

Pain elicits fear and anxiety and promotes escape, avoidance, and adaptive behaviors that are essential for survival. When pain persists, motivational priority and attention shift to pain-related information. Such a shift often results in impaired functionality, leading to maladaptive pain-related fear and anxiety and escape and avoidance behaviors. Neuroimaging studies in chronic pain patients have established that brain activity, especially in cortical and mesolimbic regions, is different from activity observed during acute pain in control subjects. In this review, we discuss the psychophysiological and neuronal factors that may be associated with the transition to chronic pain. We review information from human studies on neural circuits involved in emotional and motivational pain processing and how these circuits are altered in chronic pain conditions. We then highlight findings from animal research that can increase our understanding of the molecular and cellular mechanisms underlying emotional-motivational pain processing in the brain. Finally, we discuss how translational approaches incorporating results from both human and animal investigations may aid in accelerating the discovery of therapies.

D'Alberto, N., Chaarani, B., Orr, C. A., Spechler, P. A., …, Nees, F., …, & Garavan, H. (2018). Individual differences in stop-related activity are inflated by the adaptive algorithm in the stop signal task. Hum. Brain Mapp., 39(8), 3263–3276. PMID:29656430, doi:10.1002/hbm.24075.

Gonzalez, D. A., Jia, T., Pinzón, J. H., Acevedo, S. F., …, IMAGEN Consortium, & Rothenfluh, A. (2018). The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans. Mol. Psychiatry, 23(3), 621–628. PMID:28607459, doi:10.1038/mp.2017.112.

Ubiquitously expressed genes have been implicated in a variety of specific behaviors, including responses to ethanol. However, the mechanisms that confer this behavioral specificity have remained elusive. Previously, we showed that the ubiquitously expressed small GTPase Arf6 is required for normal ethanol-induced sedation in adult Drosophila. Here, we show that this behavioral response also requires Efa6, one of (at least) three Drosophila Arf6 guanine exchange factors. Ethanol-naive Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared with wild-type flies. In contrast to wild-type flies, both Arf6 and Efa6 mutants preferred alcohol-containing food without prior ethanol experience. An analysis of the human ortholog of Arf6 and orthologs of Efa6 (PSD1-4) revealed that the minor G allele of single nucleotide polymorphism (SNP) rs13265422 in PSD3, as well as a haplotype containing rs13265422, was associated with an increased frequency of drinking and binge drinking episodes in adolescents. The same haplotype was also associated with increased alcohol dependence in an independent European cohort. Unlike the ubiquitously expressed human Arf6 GTPase, PSD3 localization is restricted to the brain, particularly the prefrontal cortex (PFC). Functional magnetic resonance imaging revealed that the same PSD3 haplotype was also associated with a differential functional magnetic resonance imaging signal in the PFC during a Go/No-Go task, which engages PFC-mediated executive control. Our translational analysis, therefore, suggests that PSD3 confers regional specificity to ubiquitous Arf6 in the PFC to modulate human alcohol-drinking behaviors.

Kaminski, J. A., Schlagenhauf, F., Rapp, M., Awasthi, S., …, Nees, F., …, & Heinz, A. (2018). Epigenetic variance in dopamine D2 receptor: a marker of IQ malleability? Transl. Psychiatry, 8(1), 169. PMID:30166545, doi:10.1038/s41398-018-0222-7.

Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the “missing heritability” between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.

Macare, C., Ducci, F., Zhang, Y., Ruggeri, B., …, IMAGEN Consortium, & Schumann, G. (2018). A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response. Eur. Neuropsychopharmacol., 28(10), 1103–1114. PMID:30104163, doi:10.1016/j.euroneuro.2018.07.101.

The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10−4) and higher plasma cotinine levels (p = 7.0 × 10−5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.

Mielenz, D., Reichel, M., Jia, T., Quinlan, E. B., …, Nees, F., …, & Müller, C. P. (2018). EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction. Mol. Psychiatry, 23(5), 1303–1319. PMID:28397836, doi:10.1038/mp.2017.63.

In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with $\beta$-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.

Millenet, S. K., Nees, F., Heintz, S., Bach, C., …, & Hohmann, S. (2018). COMT Val158Met Polymorphism and Social Impairment Interactively Affect Attention-Deficit Hyperactivity Symptoms in Healthy Adolescents. Front. Genet., 9, 284. doi:10.3389/fgene.2018.00284.

and social impairment might interactively affect ADHD symptomatology, and could thus represent significant gene-phenotypic risk factors for ADHD symptomatology. This might have interesting implications for prevention and intervention strategies with a focus on social behavior in genetically at-risk individuals.

Nees, F., & Becker, S. (2018). Psychological Processes in Chronic Pain: Influences of Reward and Fear Learning as Key Mechanisms – Behavioral Evidence, Neural Circuits, and Maladaptive Changes. Neuroscience, 387, 72–84. PMID:28890049, doi:10.1016/j.neuroscience.2017.08.051.

In the understanding of chronic pain, hypotheses derived from psychological theories, together with insights from physiological assessments and brain imaging, highlight the importance of mechanistically driven approaches. Physical system changes, for example following injury, can result in alterations of psychological processes and are accompanied by changes in corticolimbic circuits, which have been shown to be essential in emotional learning and memory, as well as reward processing and related behavior. In the present review, we thus highlight the importance of motivational, reward/pain relief, and fear learning processes in the context of chronic pain and discuss the potential of a mechanistic understanding of chronic pain within a clinical perspective, for example for the development of therapeutic strategies. We argue that changes in these mechanisms are not only characteristic for chronic pain, reflecting consequences of the disorder, but are also critically involved in the transition from acute to chronic pain states.

Nees, F., Witt, S. H., & Flor, H. (2018). Neurogenetic Approaches to Stress and Fear in Humans as Pathophysiological Mechanisms for Posttraumatic Stress Disorder. Biol. Psychiatry, 83(10), 810–820. PMID:29454655, doi:10.1016/j.biopsych.2017.12.015.

In this review article, genetic variation associated with brain responses related to acute and chronic stress reactivity and fear learning in humans is presented as an important mechanism underlying posttraumatic stress disorder. We report that genes related to the regulation of the hypothalamic-pituitary-adrenal axis, as well as genes that modulate serotonergic, dopaminergic, and neuropeptidergic functions or plasticity, play a role in this context. The strong overlap of the genetic targets involved in stress and fear learning suggests that a dimensional and mechanistic model of the development of posttraumatic stress disorder based on these constructs is promising. Genome-wide genetic analyses on fear and stress mechanisms are scarce. So far, reliable replication is still lacking for most of the molecular genetic findings, and the proportion of explained variance is rather small. Further analysis of neurogenetic stress and fear learning needs to integrate data from animal and human studies.

Nemmi, F., Nymberg, C., Darki, F., Banaschewski, T., …, Nees, F., …, & Klingberg, T. (2018). Interaction between striatal volume and DAT1 polymorphism predicts working memory development during adolescence. Dev. Cogn. Neurosci., 30, 191–199. PMID:29567584, doi:10.1016/j.dcn.2018.03.006.

There is considerable inter-individual variability in the rate at which working memory (WM) develops during childhood and adolescence, but the neural and genetic basis for these differences are poorly understood. Dopamine-related genes, striatal activation and morphology have been associated with increased WM capacity after training. Here we tested the hypothesis that these factors would also explain some of the inter-individual differences in the rate of WM development. We measured WM performance in 487 healthy subjects twice: at age 14 and 19. At age 14 subjects underwent a structural MRI scan, and genotyping of five single nucleotide polymorphisms (SNPs) in or close to the dopamine genes DRD2, DAT-1 and COMT, which have previously been associated with gains in WM after WM training. We then analyzed which biological factors predicted the rate of increase in WM between ages 14 and 19. We found a significant interaction between putamen size and DAT1/SLC6A3 rs40184 polymorphism, such that TC heterozygotes with a larger putamen at age 14 showed greater WM improvement at age 19. The effect of the DAT1 polymorphism on WM development was exerted in interaction with striatal morphology. These results suggest that development of WM partially share neuro-physiological mechanism with training-induced plasticity.

O'Halloran, L., Cao, Z., Ruddy, K., Jollans, L., …, Nees, F., …, & Whelan, R. (2018). Neural circuitry underlying sustained attention in healthy adolescents and in ADHD symptomatology. Neuroimage, 169, 395–406. PMID:29274748, doi:10.1016/j.neuroimage.2017.12.030.

Papanastasiou, E., Mouchlianitis, E., Joyce, D. W., McGuire, P., …, Nees, F., …, & Shergill, S. (2018). Examination of the Neural Basis of Psychoticlike Experiences in Adolescence During Reward Processing. JAMA Psychiatry, 75(10), 1043. doi:10.1001/jamapsychiatry.2018.1973.
Quinlan, E. B., Barker, E. D., Luo, Q., Banaschewski, T., …, Nees, F., …, & Schumann, G. (2018). Peer victimization and its impact on adolescent brain development and psychopathology. Mol. Psychiatry. doi:10.1038/s41380-018-0297-9.

Chronic peer victimization has long-term impacts on mental health; however, the biological mediators of this adverse relationship are unknown. We sought to determine whether adolescent brain development is involved in mediating the effect of peer victimization on psychopathology. We included participants (n = 682) from the longitudinal IMAGEN study with both peer victimization and neuroimaging data. Latent profile analysis identified groups of adolescents with different experiential patterns of victimization. We then associated the victimization trajectories and brain volume changes with depression, generalized anxiety, and hyperactivity symptoms at age 19. Repeated measures ANOVA revealed time-by-victimization interactions on left putamen volume (F = 4.38, p = 0.037). Changes in left putamen volume were negatively associated with generalized anxiety (t = −2.32, p = 0.020). Notably, peer victimization was indirectly associated with generalized anxiety via decreases in putamen volume (95% CI = 0.004–0.109). This was also true for the left caudate (95% CI = 0.002–0.099). These data suggest that the experience of chronic peer victimization during adolescence might induce psychopathology-relevant deviations from normative brain development. Early peer victimization interventions could prevent such pathological changes.

Ruggeri, B., Macare, C., Stopponi, S., Jia, T., …, Nees, F., …, & Schumann, G. (2018). Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents. J. Child Psychol. Psychiatry Allied Discip., 59(6), 650–658. PMID:29197086, doi:10.1111/jcpp.12843.

Background: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders. Methods: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity. Results: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens. Conclusions: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

Siehl, S., King, J. A., Burgess, N., Flor, H., & Nees, F. (2018). Structural white matter changes in adults and children with posttraumatic stress disorder: A systematic review and meta-analysis. NeuroImage Clin., 19(February), 581–598. PMID:29984166, doi:10.1016/j.nicl.2018.05.013.

White matter plasticity occurs throughout life due to learning and can be a protective factor against as well as a vulnerability factor for the development of mental disorders. In this systematic review we summarize findings on structural white matter changes in children and adults with posttraumatic stress disorder (PTSD) and relate them to theoretical accounts of the pathophysiology of PTSD with a focus on the disturbed processing of contexts and associated problems in emotional and cognitive processing and PTSD symptomatology. We particularly examine studies reporting fractional anisotropy (FA) measured with diffusion tensor imaging (DTI). We further subdivided the studies in adult-onset PTSD with traumatic experience in adulthood, adult-onset PTSD with traumatic experience in childhood and children with PTSD. We included 30 studies comprising almost 1700 participants with 450 adults and 300 children suffering from PTSD. Our systematic review showed that for children with PTSD and adult-onset PTSD with childhood trauma, a decrease in FA in the corpus collosum, most prominently in the anterior and posterior midbody, the isthmus and splenium were reported. For adult-onset PTSD with traumatic experience in adulthood, changes in FA in the anterior and posterior part of the cingulum, the superior longitudinal fasciculus and frontal regions were found. Using GingerAle, we also performed a coordinate-based meta-analysis of 14 studies of adult-onset PTSD with traumatic experience in adulthood and did not find any significant clusters. Our results suggest that changes in white matter microstructure vary depending on traumatic experience and are associated with changes in brain circuits related to the processing of contexts. Finally, we present methodological considerations for future studies.

Velthorst, E., Froudist-Walsh, S., Stahl, E., Ruderfer, D., …, Nees, F., …, & Martin, J. (2018). Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis. Transl. Psychiatry, 8(1), 204. PMID:30258131, doi:10.1038/s41398-018-0229-0.

While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.

Vulser, H., Paillère-Martinot, M. L., Artiges, E., Miranda, R., …, Nees, F., …, & Lemaître, H. (2018). Early variations in white matter microstructure and depression outcome in adolescents with subthreshold depression. Am. J. Psychiatry, 175(12), 1255–1264. PMID:30111185, doi:10.1176/appi.ajp.2018.17070825.

Objective: White matter microstructure alterations have recently been associated with depressive episodes during adolescence, but it is unknown whether they predate depression. The authors investigated whether subthreshold depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome. Method: Adolescents with subthreshold depression (N=96) and healthy control subjects (N=336) drawn from a community-based cohort were compared using diffusion tensor imaging and whole brain tract-based spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followed up at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines spreading from the regions identified in the TBSS analysis and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. The authors searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold depression and depression at follow-up, and then explored the specificity of the findings. Results: Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between subthreshold depression at baseline and depression at follow-up was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression. Conclusions: Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex may denote a higher risk of transition to depression in adolescents.

Zaehringer, J., Falquez, R., Schubert, A.-L., Nees, F., & Barnow, S. (2018). Neural correlates of reappraisal considering working memory capacity and cognitive flexibility. Brain Imaging Behav., 12(6), 1529–1543. PMID:29318489, doi:10.1007/s11682-017-9788-6.

Cognitive reappraisal of emotion is strongly related to long-term mental health. Therefore, the exploration of underlying cognitive and neural mechanisms has become an essential focus of research. Considering that reappraisal and executive functions rely on a similar brain network, the question arises whether behavioral differences in executive functions modulate neural activity during reappraisal. Using functional neuroimaging, the present study aimed to analyze the role of working memory capacity (WMC) and cognitive flexibility in brain activity during down-regulation of negative emotions by reappraisal in N = 20 healthy participants. Results suggests that WMC and cognitive flexibility were negatively correlated with prefrontal activity during reappraisal condition. Here, results also revealed a negative correlation between cognitive flexibility and amygdala activation. These findings provide first hints that (1) individuals with lower WMC and lower cognitive flexibility might need more higher-order cognitive neural resources in order to down-regulate negative emotions and (2) cognitive flexibility relates to emotional reactivity during reappraisal.

Zidda, F., Andoh, J., Pohlack, S. T., Winkelmann, T., …, Nees, F., & Flor, H. (2018). Default mode network connectivity of fear- and anxiety-related cue and context conditioning. Neuroimage, 165, 190–199. PMID:29050910, doi:10.1016/j.neuroimage.2017.10.024.

Classical fear conditioning is an important mechanism to adequately respond and adapt to environmental threats and has been related to the development of fear and anxiety. Both cue and context conditioning have been studied but little is known about their relation to relevant resting state networks. The default mode network (DMN) has been reported to be involved in affective learning and described as facilitating a state of readiness in responding to environmental changes. We examined resting state brain connectivity patterns of the default mode network (DMN) in 119 healthy volunteers. Specifically, we carried out correlation analyses between the DMN and skin conductance responses (SCRs) as well as arousal, valence and contingency ratings during learning. In addition, we examined the role of trait anxiety. Two different DMN patterns were identified in which stronger connectivity was linked to lower differential SCRs during fear and anxiety learning. One was related to cue conditioning and involved the amygdala and the medial prefrontal cortex, and one was associated with context conditioning and included the hippocampal formation and sensorimotor areas. These results were replicated in an independent sample. Functional connectivity of the DMN with these key regions at rest was also predictive of trait anxiety but this association could not be replicated in the second sample. We showed that DMN connectivity is differently associated with cued versus contextual learning mechanisms. Uncovering individual differences in baseline network connectivity of the DMN with these key regions might lead to a better understanding of fear and anxiety. Such findings could indeed help to identify vulnerability factors linked to network alterations at rest with dysregulation of learning processes involved in the pathophysiology of stress and anxiety disorders.

#### 2017

Albaugh, M. D., Orr, C. A., Chaarani, B., Althoff, R. R., …, Nees, F., …, & Potter, A. S. (2017). Inattention and Reaction Time Variability Are Linked to Ventromedial Prefrontal Volume in Adolescents. Biol. Psychiatry, 82(9), 660–668. PMID:28237458, doi:10.1016/j.biopsych.2017.01.003.

Bartholdy, S., Allen, K., Hodsoll, J., O'Daly, O. G., …, Nees, F., …, & Schmidt, U. (2017). Identifying disordered eating behaviours in adolescents: how do parent and adolescent reports differ by sex and age? Eur. Child Adolesc. Psychiatry, 26(6), 691–701. PMID:28050706, doi:10.1007/s00787-016-0935-1.

This study investigated the prevalence of disordered eating cognitions and behaviours across mid-adolescence in a large European sample, and explored the extent to which prevalence ratings were affected by informant (parent/adolescent), or the sex or age of the adolescent. The Development and Well-Being Assessment was completed by parent–adolescent dyads at age 14 (n = 2225) and again at age 16 (n = 1607) to explore the prevalence of 7 eating disorder symptoms (binge eating, purging, fear of weight gain, distress over shape/weight, avoidance of fattening foods, food restriction, and exercise for weight loss). Informant agreement was assessed using kappa coefficients. Generalised estimating equations were performed to explore the impact of age, sex and informant on symptom prevalence. Slight to fair agreement was observed between parent and adolescent reports (kappa estimates between 0.045 and 0.318); however, this was largely driven by agreement on the absence of behaviours. Disordered eating behaviours were more consistently endorsed amongst girls compared to boys (odds ratios: 2.96–5.90) and by adolescents compared to their parents (odds ratios: 2.71–9.05). Our data are consistent with previous findings in epidemiological studies. The findings suggest that sex-related differences in the prevalence of disordered eating behaviour are established by mid-adolescence. The greater prevalence rates obtained from adolescent compared to parent reports may be due to the secretive nature of the behaviours and/or lack of awareness by parents. If adolescent reports are overlooked, the disordered behaviour may have a greater opportunity to become more entrenched.

Bourque, J., Spechler, P. A., Potvin, S., Whelan, R., …, Nees, F., …, & Conrod, P. J. (2017). Functional neuroimaging predictors of self-reported psychotic symptoms in adolescents. Am. J. Psychiatry, 174(6), 566–575. PMID:28320226, doi:10.1176/appi.ajp.2017.16080897.

Objective: This study investigated the neural correlates of psychotic-like experiences in youths during tasks involving inhibitory control, reward anticipation, and emotion processing. A secondary aim was to test whether these neurofunctional correlates of risk were predictive of psychotic symptoms 2 years later. Method: Functional imaging responses to three paradigms- the stop-signal, monetary incentive delay, and faces tasks- were collected in youths at age 14, as part of the IMAGEN study. At baseline, youths from London and Dublin sites were assessed on psychotic-like experiences, and those reporting significant experiences were compared with matched control subjects. Significant brain activity differences between the groups were used to predict, with cross-validation, the presence of psychotic symptoms in the context of mood fluctuation at age 16, assessed in the full sample. These prediction analyses were conducted with the London-Dublin subsample (N=246) and the full sample (N=1,196). Results: Relative to control subjects, youths reporting psychotic-like experiencesshowed increased hippocampus/ amygdala activity during processing of neutral faces and reduced dorsolateral prefrontal activity during failed inhibition. The most prominent regional difference for classifying 16-year-olds with mood fluctuation and psychotic symptoms relative to the control groups (those with mood fluctuations but no psychotic symptoms and those with no mood symptoms) was hyperactivation of the hippocampus/ amygdala, when controlling for baseline psychotic-like experiences and cannabis use. Conclusions: The results stress the importance of the limbic network's increased response to neutral facial stimuli as a marker of the extended psychosis phenotype. These findings might help to guide early intervention strategies for at-risk youths.

Büchel, C., Peters, J., Banaschewski, T., Bokde, A. L. W., …, Nees, F., …, & Knutson, B. (2017). Blunted ventral striatal responses to anticipated rewards foreshadow problematic drug use in novelty-seeking adolescents. Nat. Commun., 8, 14140. PMID:28221370, doi:10.1038/ncomms14140.

Novelty-seeking tendencies in adolescents may promote innovation as well as problematic impulsive behaviour, including drug abuse. Previous research has not clarified whether neural hyper- or hypo-responsiveness to anticipated rewards promotes vulnerability in these individuals. Here we use a longitudinal design to track 144 novelty-seeking adolescents at age 14 and 16 to determine whether neural activity in response to anticipated rewards predicts problematic drug use. We find that diminished BOLD activity in mesolimbic (ventral striatal and midbrain) and prefrontal cortical (dorsolateral prefrontal cortex) regions during reward anticipation at age 14 predicts problematic drug use at age 16. Lower psychometric conscientiousness and steeper discounting of future rewards at age 14 also predicts problematic drug use at age 16, but the neural responses independently predict more variance than psychometric measures. Together, these findings suggest that diminished neural responses to anticipated rewards in novelty-seeking adolescents may increase vulnerability to future problematic drug use.

Cacciaglia, R., Nees, F., Grimm, O., Ridder, S., …, & Flor, H. (2017). Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: Implications for psychopathology. Psychoneuroendocrinology, 76, 19–28. PMID:27871027, doi:10.1016/j.psyneuen.2016.11.012.

Stress exposure causes a structural reorganization in neurons of the amygdala. In particular, animal models have repeatedly shown that both acute and chronic stress induce neuronal hypertrophy and volumetric increase in the lateral and basolateral nuclei of amygdala. These effects are visible on the behavioral level, where stress enhances anxiety behaviors and provokes greater fear learning. We assessed stress and anxiety levels in a group of 18 healthy human trauma-exposed individuals (TR group) compared to 18 non-exposed matched controls (HC group), and related these measurements to amygdala volume. Traumas included unexpected adverse experiences such as vehicle accidents or sudden loss of a loved one. As a measure of aversive learning, we implemented a cued fear conditioning paradigm. Additionally, to provide a biological marker of chronic stress, we measured the sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis using a dexamethasone suppression test. Compared to the HC, the TR group showed significantly higher levels of chronic stress, current stress and trait anxiety, as well as increased volume of the left amygdala. Specifically, we observed a focal enlargement in its lateral portion, in line with previous animal data. Compared to HC, the TR group also showed enhanced late acquisition of conditioned fear and deficient extinction learning, as well as salivary cortisol hypo-suppression to dexamethasone. Left amygdala volumes positively correlated with suppressed morning salivary cortisol. Our results indicate differences in trauma-exposed individuals which resemble those previously reported in animals exposed to stress and in patients with post-traumatic stress disorder and depression. These data provide new insights into the mechanisms through which traumatic stress might prompt vulnerability for psychopathology.

Cavalli, J., Ruttorf, M., Pahi, M. R., Zidda, F., …, & Nees, F. (2017). Oxytocin differentially modulates pavlovian cue and context fear acquisition. Soc. Cogn. Affect. Neurosci., 12(6), 976–983. PMID:28402515, doi:10.1093/scan/nsx028.

Fear acquisition and extinction have been demonstrated as core mechanisms for the development and maintenance of mental disorders, with different contributions of processing cues vs contexts. The hypothalamic peptide oxytocin (OXT) may have a prominent role in this context, as it has been shown to affect fear learning. However, investigations have focused on cue conditioning, and fear extinction. Its differential role for cue and context fear acquisition is still not known. In a randomized, double-blind, placebo (PLC)-controlled design, we administered an intranasal dose of OXT or PLC before the acquisition of cue and context fear conditioning in healthy individuals (n = 52), and assessed brain responses, skin conductance responses and self-reports (valence/arousal/contingency). OXT compared with PLC significantly induced decreased responses in the nucleus accumbens during early cue and context acquisition, and decreased responses of the anterior cingulate cortex and insula during early as well as increased hippocampal response during late context, but not cue acquisition. The OXT group additionally showed significantly higher arousal in late cue and context acquisition. OXT modulates various aspects of cue and context conditioning, which is relevant from a mechanism-based perspective and might have implications for the treatment of fear and anxiety.

Deng, W., Rolls, E. T., Ji, X., Robbins, T. W., …, Nees, F., …, & Feng, J. (2017). Separate neural systems for behavioral change and for emotional responses to failure during behavioral inhibition. Hum. Brain Mapp., 38(7), 3527–3537. PMID:28429498, doi:10.1002/hbm.23607.

To analyze the involvement of different brain regions in behavioral inhibition and impulsiveness, differences in activation were investigated in fMRI data from a response inhibition task, the stop-signal task, in 1709 participants. First, areas activated more in stop-success (SS) than stop-failure (SF) included the lateral orbitofrontal cortex (OFC) extending into the inferior frontal gyrus (ventrolateral prefrontal cortex, BA 47/12), and the dorsolateral prefrontal cortex (DLPFC). Second, the anterior cingulate and anterior insula (AI) were activated more on failure trials, specifically in SF versus SS. The interaction between brain region and SS versus SF activations was significant (P = 5.6 * 10 -8 ). The results provide new evidence from this “big data” investigation consistent with the hypotheses that the lateral OFC is involved in the stop-related processing that inhibits the action; that the DLPFC is involved in attentional processes that influence task performance; and that the AI and anterior cingulate are involved in emotional processes when failure occurs. The investigation thus emphasizes the role of the human lateral OFC BA 47/12 in changing behavior, and inhibiting behavior when necessary. A very similar area in BA47/12 is involved in changing behavior when an expected reward is not obtained, and has been shown to have high functional connectivity in depression.

Duka, T., Nikolaou, K., King, S. L., Banaschewski, T., …, IMAGEN Consortium, & Stephens, D. N. (2017). GABRB1 Single Nucleotide Polymorphism Associated with Altered Brain Responses (but not Performance) during Measures of Impulsivity and Reward Sensitivity in Human Adolescents. Front. Behav. Neurosci., 11. doi:10.3389/fnbeh.2017.00024.
Guadalupe, T., Mathias, S. R., van Erp, T. G. M., Whelan, C. D., …, Nees, F., …, & Francks, C. (2017). Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex. Brain Imaging Behav., 11(5), 1497–1514. PMID:27738994, doi:10.1007/s11682-016-9629-z.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Khan, W., Giampietro, V., Banaschewski, T., Barker, G. J., …, Nees, F., …, & Simmons, A. (2017). A Multi-Cohort Study of ApoE ϵ 4 and Amyloid-β Effects on the Hippocampus in Alzheimer's Disease. J. Alzheimer's Dis., 56(3), 1159–1174. PMID:28157104, doi:10.3233/JAD-161097.

The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer's disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n 1,781), we compared the effect of APOE and amyloid-$\beta$ (A$\beta$) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n 1,387) was also used to compared hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in ϵ4 carriers with positron emission tomography A$\beta$ who were dichotomized (A$\beta$/A$\beta$-) using previous cut-offs. We found a linear reduction in hippocampal volumes with ϵ4 carriers possessing the smallest volumes, ϵ3 carriers possessing intermediate volumes, and ϵ2 carriers possessing the largest volumes. Moreover, AD and MCI ϵ4 carriers possessed the smallest hippocampal volumes and control ϵ2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ϵ4 and A$\beta$ had the lowest hippocampal volumes when compared to A$\beta$- ϵ4 carriers, suggesting a synergistic relationship between APOE ϵ4 and A$\beta$. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ϵ4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.

Lonsdorf, T. B.*, Menz, M. M.*, Andreatta, M., Fullana, M. A., …, Nees, F., …, & Merz, C. J. (2017). Don't fear ‘fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neurosci. Biobehav. Rev., 77, 247–285. PMID:28263758, doi:10.1016/j.neubiorev.2017.02.026.

The so-called ‘replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

Mackey, S., Chaarani, B., Kan, K. J., Spechler, P. A., …, Nees, F., …, & Garavan, H. (2017). Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior. Biol. Psychiatry, 82(4), 275–282. PMID:26971049, doi:10.1016/j.biopsych.2015.12.027.

Background Individual differences in impulsivity and early adversity are known to be strong predictors of adolescent antisocial behavior. However, the neurobiological bases of impulsivity and their relation to antisocial behavior and adversity are poorly understood. Methods Impulsivity was estimated with a temporal discounting task. Voxel-based morphometry was used to determine the brain structural correlates of temporal discounting in a large cohort (n = 1830) of 14- to 15-year-old children. Mediation analysis was then used to determine whether the volumes of brain regions associated with temporal discounting mediate the relation between adverse life events (e.g., family conflict, serious accidents) and antisocial behaviors (e.g., precocious sexual activity, bullying, illicit substance use). Results Greater temporal discounting (more impulsivity) was associated with 1) lower volume in frontomedial cortex and bilateral insula and 2) greater volume in a subcortical region encompassing the ventral striatum, hypothalamus and anterior thalamus. The volume ratio between these cortical and subcortical regions was found to partially mediate the relation between adverse life events and antisocial behavior. Conclusions Temporal discounting is related to regions of the brain involved in reward processing and interoception. The results support a developmental imbalance model of impulsivity and are consistent with the idea that negative environmental factors can alter the developing brain in ways that promote antisocial behavior.

Nees, F., Becker, S., Millenet, S. K., Banaschewski, T., …, & Flor, H. (2017). Brain substrates of reward processing and the µ-opioid receptor: A pathway into pain? Pain, 158(2), 212–219. PMID:28092323, doi:10.1097/j.pain.0000000000000720.

The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Children's Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T-allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition.

Quinlan, E. B.*, Cattrell, A.*, Jia, T., Artiges, E., …, Nees, F., …, & Schumann, G. (2017). Psychosocial Stress and Brain Function in Adolescent Psychopathology. Am. J. Psychiatry, 174(8), 785–794. PMID:28618856, doi:10.1176/appi.ajp.2017.16040464.

Objective: The authors sought to explore how conduct, hyperactivity/inattention, and emotional symptoms are associated with neural reactivity to social-emotional stimuli, and the extent to which psychosocial stress modulates these relationships. Method: Participants were community adolescents recruited as part of the European IMAGEN study. Bilateral amygdala regions of interest were used to assess the relationship between the three symptomdomains and functionalMRI neural reactivity during passive viewing of dynamic angry and neutral facial expressions. Exploratory functional connectivity and whole brain multiple regression approaches were used to analyze how the symptoms and psychosocial stress relate to other brain regions. Results: In response to the social-emotional stimuli, adolescents with high levels of conduct or hyperactivity/ inattention symptoms who had also experienced a greater number of stressful life events showed hyperactivity of the amygdala and several regions across the brain. This effect was not observed with emotional symptoms. A cluster in the midcingulate was found to be common to both conduct problems and hyperactivity symptoms. Exploratory functional connectivity analyses suggested that amygdalaprecuneus connectivity is associated with hyperactivity/ inattention symptoms. Conclusions: The results link hyperactive amygdala responses and regions critical for top-down emotional processing with high levels of psychosocial stress in individuals with greater conduct and hyperactivity/inattention symptoms. This work highlights the importance of studying how psychosocial stress affects functional brain responses to social-emotional stimuli, particularly in adolescents with externalizing symptoms.

Sadaghiani, S., Ng, B., Altmann, A., Poline, J.-B., …, Nees, F., …, & Greicius, M. (2017). Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control. J. Neurosci., 37(40), 9657–9666. PMID:28877969, doi:10.1523/JNEUROSCI.0991-17.2017.

The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N = 1586, behavioral total N = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor $\alpha$4$\beta$2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence p = 1.33 * 10−5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities.

Winkelmann, T., Thayer, J. F., Pohlack, S. T., Nees, F., …, & Flor, H. (2017). Structural brain correlates of heart rate variability in a healthy young adult population. Brain Struct. Funct., 222(2), 1061–1068. PMID:26801184, doi:10.1007/s00429-016-1185-1.

The high frequency component of heart rate variability (HRV) has reliably been shown to serve as an index of autonomic inhibitory control and is increasingly considered as a biomarker of adaptability and health. While several functional neuroimaging studies identified associations between regional cerebral blood flow and HRV, studies on structural brain correlates of HRV are scarce. We investigated whether interindividual differences in HRV are related to brain morphology in healthy humans. Thirty participants underwent HRV recording at rest subsequent to structural magnetic resonance imaging. Cortical reconstruction and subcortical volumetry were performed with the Freesurfer image analysis suite. The amount of resting HRV was positively correlated with the cortical thickness of an area within the right anterior midcingulate cortex (aMCC). Consistent with existing studies implicating forebrain regions in cardiac regulation, our findings show that the thickness of the right aMCC is associated with the degree of parasympathetic regulation of heart rate. Evidence for the neural correlates of interindividual differences in HRV may complement our understanding of the mechanisms underlying the association between HRV and self-regulatory capacity.

Xu, B., Jia, T., Macare, C., Banaschewski, T., …, Nees, F., …, & Mennigen, E. (2017). Impact of a Common Genetic Variation Associated With Putamen Volume on Neural Mechanisms of Attention-Deficit/Hyperactivity Disorder. J. Am. Acad. Child Adolesc. Psychiatry, 56(5), 436—-444.e4. PMID:28433093, doi:10.1016/j.jaac.2017.02.009.

#### 2016

Burt, K. B., Whelan, R., Conrod, P. J., Banaschewski, T., …, Nees, F., …, & Garavan, H. (2016). Structural brain correlates of adolescent resilience. J. Child Psychol. Psychiatry Allied Discip., 57(11), 1287–1296. PMID:27079174, doi:10.1111/jcpp.12552.

Castellanos-Ryan, N., Briere, F. N., O'Leary-Barrett, M., Banaschewski, T., …, Nees, F., …, IMAGEN Consortium, & Conrod, P. J. (2016). The structure of psychopathology in adolescence and its common personality and cognitive correlates. J. Abnorm. Psychol., 125(8), 1039–1052. PMID:27819466, doi:10.1037/abn0000193.

The traditional view that mental disorders are distinct, categorical disorders has been challenged by evidence that disorders are highly comorbid and exist on a continuum (e.g., Caspi et al., 2014; Tackett et al., 2013). The first objective of this study was to use structural equation modeling to model the structure of psychopathology in an adolescent community-based sample (N = 2,144) including conduct disorder, attention-deficit/hyperactivity disorder (ADHD), oppositional-defiant disorder (ODD), obsessive-compulsive disorder, eating disorders, substance use, anxiety, depression, phobias, and other emotional symptoms, assessed at 16 years. The second objective was to identify common personality and cognitive correlates of psychopathology, assessed at 14 years. Results showed that psychopathology at 16 years fit 2 bifactor models equally well: (a) a bifactor model, reflecting a general psychopathology factor, as well as specific externalizing (representing mainly substance misuse and low ADHD) and internalizing factors; and (b) a bifactor model with a general psychopathology factor and 3 specific externalizing (representing mainly ADHD and ODD), substance use and internalizing factors. The general psychopathology factor was related to high disinhibition/impulsivity, low agreeableness, high neuroticism and hopelessness, high delay-discounting, poor response inhibition and low performance IQ. Substance use was specifically related to high novelty-seeking, sensation-seeking, extraversion, high verbal IQ, and risk-taking. Internalizing psychopathology was specifically related to high neuroticism, hopelessness and anxiety-sensitivity, low novelty-seeking and extraversion, and an attentional bias toward negatively valenced verbal stimuli. Findings reveal several nonspecific or transdiagnostic personality and cognitive factors that may be targeted in new interventions to potentially prevent the development of multiple psychopathologies.

Diener, S. J.*, Nees, F.*, Wessa, M., Wirtz, G., …, & Flor, H. (2016). Reduced amygdala responsivity during conditioning to trauma-related stimuli in posttraumatic stress disorder. Psychophysiology, 53(10), 1460–1471. PMID:27412783, doi:10.1111/psyp.12699.

Exaggerated conditioned fear responses and impaired extinction along with amygdala overactivation have been observed in posttraumatic stress disorder (PTSD). These fear responses might be triggered by cues related to the trauma through higher-order conditioning, where reminders of the trauma may serve as unconditioned stimuli (US) and could maintain the fear response. We compared arousal, valence, and US expectancy ratings and BOLD brain responses using fMRI in 14 traumatized persons with PTSD and 14 without PTSD (NPTSD) and 13 matched healthy controls (HC) in a differential aversive conditioning paradigm. The US were trauma-specific pictures for the PTSD and NPTSD group and equally aversive and arousing for the HC; the conditioned stimuli (CS) were graphic displays. During conditioning, the PTSD patients compared to the NPTSD and HC indicated higher arousal to the conditioned stimulus that was paired with the trauma picture (CS+) compared to the unpaired (CS-), increased dissociation during acquisition and extinction, and failure to extinguish the CS/US-association compared to NPTSD. During early and late acquisition, the PTSD patients showed a significantly lower amygdala activation to CS+ versus CS- and a negative interaction between activation in the amygdala and dorsolateral prefrontal cortex (PFC), while NPTSD and HC displayed a negative interaction between amygdala and medial PFC. These findings suggest maladaptive anticipatory coping with trauma-related stimuli in patients with PTSD, indicated by enhanced conditioning, with related abnormal amygdala reactivity and connectivity, and delayed extinction.

Dinu-Biringer, R., Nees, F., Falquez, R., Berger, M., & Barnow, S. (2016). Different roads to the same destination - The impact of impulsivity on decision-making processes under risk within a rewarding context in a healthy male sample. Psychiatry Res. - Neuroimaging, 248, 12–22. PMID:26786151, doi:10.1016/j.pscychresns.2016.01.012.

The results of research about the influences of impulsivity on decision-making in situations of risk have been inconsistent. In this study, we used functional magnetic resonance imaging to examine the neural correlates of decision-making under risk in 12 impulsive, as defined by the Barratt Impulsiveness Scale-11, and 13 normal men. Although both groups showed similar decision-making behavior, neural activation regarding decision-making processes differed significantly. Impulsive persons revealed stronger activation in the (ventro-) medial prefrontal cortex and less deactivation of the orbitofrontal cortex while playing for potential gains. These brain regions might be associated with the emotional components of decision-making processes. Significant differences in brain areas linked to cognitive decision-making components were not found. This activation pattern might be seen as an indication for a hypersensitivity to rewarding cues in impulsive persons and might be linked to the propensity for inappropriate risk-taking behavior in persons with more extreme impulsivity levels, especially in situations in which they have a strong emotional involvement in the decision process.

Ewald, A.*, Becker, S.*, Heinrich, A., Banaschewski, T., …, & Nees, F. (2016). The role of the cannabinoid receptor in adolescents′ processing of facial expressions. Eur. J. Neurosci., 43(1), 98–105. PMID:26527537, doi:10.1111/ejn.13118.

Falquez, R., Lang, S., Dinu-Biringer, R., Nees, F., …, & Barnow, S. (2016). On the relationship between negative affective priming and prefrontal cognitive control mechanisms. Cogn. Emot., 30(2), 225–244. PMID:25648386, doi:10.1080/02699931.2014.994476.

Although several studies have examined inhibition of affective stimuli, valence-dependent cognitive control effects remain poorly understood. Behavioural and functional imaging (functional magnetic resonance imaging) data were collected from 17 healthy participants to examine neural correlates of the Negative Affective Priming (NAP) task. We created relative ratio scores considering the reaction times of prime trials in order to assess the amount of interference after the presentation of negative and positive distracter words. Behavioural results showed an attenuated NAP effect for negative distracters compared to neutral stimuli. Furthermore, priming negative distracters generated more interference by reacting to the probe target than positive distracters. Neuroimaging data revealed a stronger prefrontal activation during negative NAP trials compared to positive NAP and neutral control trials, which was reflected in a heightened activation of superior and middle frontal gyrus as well as parietal cortex. The findings show the impact of negative distracters on prefrontal response, contributing to the understanding of NAP effects in healthy subjects.

Gollier-Briant, F., Paillère-Martinot, M. L., Lemaître, H., Miranda, R., …, Nees, F., …, & Artiges, E. (2016). Neural correlates of three types of negative life events during angry face processing in adolescents. Soc. Cogn. Affect. Neurosci., 11(12), 1961–1969. PMID:27697987, doi:10.1093/scan/nsw100.

Negative life events (NLE) contribute to anxiety and depression disorders, but their relationship with brain functioning in adolescence has rarely been studied. We hypothesized that neural response to social threat would relate to NLE in the frontal-limbic emotional regions. Participants (N = 685) were drawn from the Imagen database of 14-year-old community adolescents recruited in schools. They underwent functional MRI while viewing angry and neutral faces, as a probe to neural response to social threat. Lifetime NLEs were assessed using the 'distress', 'family' and 'accident' subscales from a life event dimensional questionnaire. Relationships between NLE subscale scores and neural response were investigated. Links of NLE subscales scores with anxiety or depression outcomes at the age of 16 years were also investigated. Lifetime 'distress' positively correlated with ventral-lateral orbitofrontal and temporal cortex activations during angry face processing. 'Distress' scores correlated with the probabilities of meeting criteria for Generalized Anxiety Disorder or Major Depressive Disorder at the age of 16 years. Lifetime 'family' and 'accident' scores did not relate with neural response or follow-up conditions, however. Thus, different types of NLEs differentially predicted neural responses to threat during adolescence, and differentially predicted a de novo internalizing condition 2 years later. The deleterious effect of self-referential NLEs is suggested.

Heinrich, A., Schumann, G., Flor, H., & Nees, F. (2016). Identification of key items regarding personality, environment, and life events to assess risk and resilience factors for harmful alcohol drinking in adolescents. Alcohol Alcohol., 51(6), 710–715. PMID:27001996, doi:10.1093/alcalc/agw012.

Aims: Alcohol misuse often develops during adolescence involving interacting factors deriving from personality, environment and life events that can be assessed with well-established instruments. However, for specific research purposes, involving the assessment of large data sets, it may be beneficial having a short tool of key items representing the most important risk factors. Methods: We identified a set of key items from standard questionnaires assessed in about 2000 adolescents. In our longitudinal study we identified important items on personality, environment, and life events explaining alcohol drinking behaviour at the age of 14 years and the increase of alcohol consumption 2 years later. Results: The key items explained 33.4% of variance in alcohol drinking behaviour (vs. 34.8% for original battery) and can be completed in six minutes. Conclusions: Our item list represents a powerful easy-to-use tool for the examination of alcohol drinking behaviour in adolescents.

Heinrich, A., Müller, K. U., Banaschewski, T., Barker, G. J., …, & Nees, F. (2016). Prediction of alcohol drinking in adolescents: Personality-traits, behavior, brain responses, and genetic variations in the context of reward sensitivity. Biol. Psychol., 118, 79–87. PMID:27180911, doi:10.1016/j.biopsycho.2016.05.002.

Adolescence is a time that can set the course of alcohol abuse later in life. Sensitivity to reward on multiple levels is a major factor in this development. We examined 736 adolescents from the IMAGEN longitudinal study for alcohol drinking during early (mean age = 14.37) and again later (mean age = 16.45) adolescence. Conducting structural equation modeling we evaluated the contribution of reward-related personality traits, behavior, brain responses and candidate genes. Personality seems to be most important in explaining alcohol drinking in early adolescence. However, genetic variations in ANKK1 (rs1800497) and HOMER1 (rs7713917) play an equal role in predicting alcohol drinking two years later and are most important in predicting the increase in alcohol consumption. We hypothesize that the initiation of alcohol use may be driven more strongly by personality while the transition to increased alcohol use is more genetically influenced.

Jia, T., Macare, C., Desrivières, S., Gonzalez, D. A., …, Nees, F., …, & Schumann, G. (2016). Neural basis of reward anticipation and its genetic determinants. Proc. Natl. Acad. Sci., 113(14), 3879–3884. PMID:27001827, doi:10.1073/pnas.1503252113.

Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A ( VPS4A ) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila . Our data provide a neurobehavioral model explaining the heterogeneity of reward-related behaviors and generate a hypothesis accounting for their enduring nature.

Jollans, L., Zhipeng, C., Icke, I., Greene, C., …, Nees, F., …, & Whelan, R. (2016). Ventral Striatum Connectivity During Reward Anticipation in Adolescent Smokers. Dev. Neuropsychol., 41(1-2), 6–21. PMID:27074029, doi:10.1080/87565641.2016.1164172.

Substance misusers, including adolescent smokers, often have reduced reward system activity during processing of non-drug rewards. Using a psychophysiological interaction approach, we examined functional connectivity with the ventral striatum during reward anticipation in a large (N = 206) sample of adolescent smokers. Increased smoking frequency was associated with (1) increased connectivity with regions involved in saliency and valuation, including the orbitofrontal cortex and (2) reduced connectivity between the ventral striatum and regions associated with inhibition and risk aversion, including the right inferior frontal gyrus. These results demonstrate that functional connectivity during reward processing is relevant to adolescent addiction.

Kühn, S., Witt, C., Banaschewski, T., Barbot, A., …, IMAGEN Consortium, & Gallinat, J. (2016). From mother to child: orbitofrontal cortex gyrification and changes of drinking behaviour during adolescence. Addict. Biol., 21(3), 700–708. PMID:25913102, doi:10.1111/adb.12240.

Lancaster, T. M., Linden, D. E., Tansey, K. E., Banaschewski, T., …, Nees, F., …, & Schumann, G. (2016). Polygenic risk of psychosis and ventral striatal activation during reward processing in healthy adolescents. JAMA Psychiatry, 73(8), 852–861. PMID:27384424, doi:10.1001/jamapsychiatry.2016.1135.

IMPORTANCE: Psychotic disorders are characterized by attenuated activity in the brain's valuation system in key reward processing areas, such as the ventral striatum (VS), as measured with functional magnetic resonance imaging. OBJECTIVE: To examine whether common risk variants for psychosis are associated with individual variation in the VS. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of a large cohort of adolescents from the IMAGEN study (a European multicenter study of reinforcement sensitivity in adolescents) was performed from March 1, 2008, through December 31, 2011. Data analysis was conducted from October 1, 2015, to January 9, 2016. Polygenic risk profile scores (RPSs) for psychosis were generated for 1841 healthy adolescents. Sample size and characteristics varied across regression analyses, depending on mutual information available (N = 1524-1836). MAIN OUTCOMES AND MEASURES: Reward-related brain function was assessed with blood oxygen level dependency (BOLD) in the VS using the monetary incentive delay (MID) task, distinguishing reward anticipation and receipt. Behavioral impulsivity, IQ, MID task performance, and VS BOLD were regressed against psychosis RPS at 4 progressive P thresholds (P < .01, P < .05, P < .10, and P < .50 for RPS models 1-4, respectively). RESULTS: In a sample of 1841 healthy adolescents (mean age, 14.5 years; 906 boys and 935 girls), we replicated an association between increasing psychosis RPS and reduced IQ (matrix reasoning: corrected P = .003 for RPS model 2, 0.4% variance explained), supporting the validity of the psychosis RPS models. We also found a nominally significant association between increased psychosis RPS and reduced MID task performance (uncorrected P =.03 for RPS model 4, 0.2% variance explained). Our main finding was a positive association between psychosis RPS and VS BOLD during reward anticipation at all 4 psychosis RPS models and for 2 P thresholds for reward receipt (RPS models 1 and 3), correcting for the familywise error rate (0.8%-1.9% variance explained). CONCLUSIONS AND RELEVANCE: These findings support an association between psychosis RPS and VS BOLD in adolescents. Genetic risk for psychosis may shape an individual's response to rewarding stimuli.

Meyer, B. M., Huemer, J., Rabl, U., Boubela, R. N., …, Nees, F., …, & Pezawas, L. (2016). Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults. Brain Struct. Funct., 221(1), 103–114. PMID:25319752, doi:10.1007/s00429-014-0895-5.

Mikita, N., Simonoff, E., Pine, D. S., Goodman, R., …, Nees, F., …, & Stringaris, A. (2016). Disentangling the autism−anxiety overlap: fMRI of reward processing in a community-based longitudinal study. Transl. Psychiatry, 6(6), e845—-e845. PMID:27351599, doi:10.1038/tp.2016.107.

Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age = 14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2×2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.

Nees, F.*, Griebe, M.*, Ebert, A., Ruttorf, M., …, & Szabo, K. (2016). Implicit Learning in Transient Global Amnesia and the Role of Stress. Front. Behav. Neurosci., 10(NOV), 1–11. doi:10.3389/fnbeh.2016.00222.

Transient global amnesia (TGA) is a disorder with reversible anterograde disturbance of explicit memory, frequently preceded by an emotionally or physically stressful event. By using magnetic resonance imaging (MRI) following an episode of TGA, small hippocampal lesions have been observed. Hence it has been postulated that the disorder is caused by the stress-related transient inhibition of memory formation in the hippocampus. In experimental studies, stress has been shown to affect both explicit and implicit learning—the latter defined as learning and memory processes that lack conscious awareness of the information acquired. To test the hypothesis that impairment of implicit learning in TGA is present and related to stress, we determined the effect of experimental exposure to stress on hippocampal activation patterns during an implicit learning paradigm in patients who suffered a recent TGA and healthy matched control subjects. We used a hippocampus-dependent aversive learning procedure (context conditioning with the phases habituation, acquisition, and extinction) during functional MRI following experimental stress exposure (socially evaluated cold pressor test). After a control procedure, controls showed successful learning during the acquisition phase, indicated by increased valence, arousal and contingency ratings to the paired (CON+) vs. the non-paired (CON−) conditioned stimulus, and successful extinction of the conditioned responses. Following stress, acquisition was still successful, however extinction was impaired with persistently increased contingency ratings. In contrast, TGA patients showed impairment of conditioned responses and insufficient extinction after the control procedure, indicated by a lack of significant differences between CON+ and CON− for valence and arousal ratings after the acquisition phase and by significantly increased contingency ratings after the extinction. After stress, aversive learning was not successful with non-significant ratings of all parameters. Concerning brain activation patterns after the control procedure, controls showed increased hippocampal response during acquisition after the control procedure. This was not seen after stress exposure. In TGA patients, we observed an increased response in the right ventral striatum in the acquisition phase following stress. These findings suggest that alterations in implicit learning processes, including impaired hippocampal and increased striatal responses, might play a role in TGA pathophysiology, partly related to acute stress.

Parchetka, C., Strache, N., Raffaelli, B., Gemmeke, I., …, Nees, F., …, & Gallinat, J. (2016). Predictive utility of the NEO-FFI for later substance experiences among 16-year-old adolescents. J. Public Health (Bangkok)., 24(6), 489–495. doi:10.1007/s10389-016-0747-2.
Stacey, D., Lourdusamy, A., Ruggeri, B., Maroteaux, M., …, Nees, F., …, & Desrivieres, S. (2016). A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males. J. Psychiatry Neurosci., 41(2), 192–202. PMID:26679926, doi:10.1503/jpn.150138.

Background: The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2–/– mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Methods: Transcriptomic data from the nucleus accumbens (NAcc) of maleRasgrf2–/– mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). Results: The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). Limitations: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2–/– mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Conclusion: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2–/– mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.

Wicking, M., Steiger, F., Nees, F., Diener, S. J., …, & Flor, H. (2016). Deficient fear extinction memory in posttraumatic stress disorder. Neurobiol. Learn. Mem., 136, 116–126. PMID:27686278, doi:10.1016/j.nlm.2016.09.016.

Background Posttraumatic stress disorder (PTSD) might be maintained by deficient extinction memory. We used a cued fear conditioning design with extinction and a post-extinction phase to provoke the return of fear and examined the role of the interplay of amygdala, hippocampus and prefrontal regions. Methods We compared 18 PTSD patients with two healthy control groups: 18 trauma-exposed subjects without PTSD (nonPTSD) and 18 healthy controls (HC) without trauma experience. They underwent a three-day ABC-conditioning procedure in a functional magnetic resonance imaging scanner. Two geometric shapes that served as conditioned stimuli (CS) were presented in the context of virtual reality scenes. Electric painful stimuli were delivered after one of the two shapes (CS+) during acquisition (in context A), while the other (CS−) was never paired with pain. Extinction was performed in context B and extinction memory was tested in a novel context C. Results The PTSD patients showed significantly higher differential skin conductance responses than the non-PTSD and HC and higher differential amygdala and hippocampus activity than the HC in context C. In addition, elevated arousal to the CS+ during extinction and to the CS− throughout the experiment was present in the PTSD patients but self-reported differential valence or contingency were not different. During extinction recall, differential amygdala activity correlated positively with the intensity of numbing and ventromedial prefrontal cortex activity correlated positively with behavioral avoidance. Conclusions PTSD patients show heightened return of fear in neural and peripheral measures. In addition, self-reported arousal was high to both danger (CS+) and safety (CS−) cues. These results suggest that a deficient maintenance of extinction and a failure to identify safety signals might contribute to PTSD symptoms, whereas non-PTSD subjects seem to show normal responses.

Winkelmann, T., Grimm, O., Pohlack, S. T., Nees, F., …, & Flor, H. (2016). Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning. Brain Struct. Funct., 221(4), 1927–1937. PMID:25716297, doi:10.1007/s00429-015-1013-z.

The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.

#### 2015

Allgaier, N., Banaschewski, T., Barker, G. J., Bokde, A. L. W., …, Nees, F., …, IMAGEN Consortium, & Garavan, H. (2015). Nonlinear functional mapping of the human brain. arXiV. arXiv:1510.03765.

The field of neuroimaging has truly become data rich, and novel analytical methods capable of gleaning meaningful information from large stores of imaging data are in high demand. Those methods that might also be applicable on the level of individual subjects, and thus potentially useful clinically, are of special interest. In the present study, we introduce just such a method, called nonlinear functional mapping (NFM), and demonstrate its application in the analysis of resting state fMRI from a 242-subject subset of the IMAGEN project, a European study of adolescents that includes longitudinal phenotypic, behavioral, genetic, and neuroimaging data. NFM employs a computational technique inspired by biological evolution to discover and mathematically characterize interactions among ROI (regions of interest), without making linear or univariate assumptions. We show that statistics of the resulting interaction relationships comport with recent independent work, constituting a preliminary cross-validation. Furthermore, nonlinear terms are ubiquitous in the models generated by NFM, suggesting that some of the interactions characterized here are not discoverable by standard linear methods of analysis. We discuss one such nonlinear interaction in the context of a direct comparison with a procedure involving pairwise correlation, designed to be an analogous linear version of functional mapping. We find another such interaction that suggests a novel distinction in brain function between drinking and non-drinking adolescents: a tighter coupling of ROI associated with emotion, reward, and interoceptive processes such as thirst, among drinkers. Finally, we outline many improvements and extensions of the methodology to reduce computational expense, complement other analytical tools like graph-theoretic analysis, and allow for voxel level NFM to eliminate the necessity of ROI selection.

Cacciaglia, R.*, Pohlack, S. T.*, Flor, H., & Nees, F. (2015). Dissociable roles for hippocampal and amygdalar volume in human fear conditioning. Brain Struct. Funct., 220(5), 2575–2586. PMID:24903827, doi:10.1007/s00429-014-0807-8.

Fear conditioning is a basic learning process which involves the association of a formerly neutral conditioned stimulus (CS) with a biologically relevant aversive unconditioned stimulus (US). Previous studies conducted in brain-lesioned patients have shown that while the acquisition of autonomic fear responses requires an intact amygdala, a spared hippocampus is necessary for the development of the CS-US contingency awareness. Although these data have been supported by studies using functional neuroimaging techniques in healthy people, attempts to extend these findings to the morphological aspects of amygdala and hippocampus are missing. Here we tested the hypothesis that amygdalar and hippocampal volumes play dissociable roles in determining autonomic responses and contingency awareness during fear conditioning. Fifty-two healthy individuals (mean age 21.83) underwent high-resolution magnetic resonance imaging. We used a differential delay fear conditioning paradigm while assessing skin conductance responses (SCRs), subjective ratings of CS-US contingency, as well as emotional valence and perceived arousal. Left amygdalar volume significantly predicted the magnitude of differential SCRs during fear acquisition, but had no impact on contingency learning. Conversely, bilateral hippocampal volumes were significantly related to contingency ratings, but not to SCRs. Moreover, left amygdalar volume predicted SCRs to the reinforced CS alone, but not those elicited by the US. Our findings bridge the gap between previous lesion and functional imaging studies, by showing that amygdalar and hippocampal volumes differentially modulate the acquisition of conditioned fear. Further, our results reveal that the morphology of these limbic structures moderate learning and memory already in healthy persons.

Cury, C., Toro, R., Cohen, F., Fischer, C., …, Nees, F., …, & Colliot, O. (2015). Incomplete hippocampal inversion: A comprehensive MRI study of over 2000 subjects. Front. Neuroanat., 9(DEC), 160. doi:10.3389/fnana.2015.00160.

The incomplete-hippocampal-inversion (IHI), also known as malrotation, is an atypical anatomical pattern of the hippocampus, which has been reported in healthy subjects in different studies. However, extensive characterization of IHI in a large sample has not yet been performed. Furthermore, it is unclear whether IHI are restricted to the medial-temporal lobe or are associated with more extensive anatomical changes. Here, we studied the characteristics of IHI in a community-based sample of 2008 subjects of the IMAGEN database and their association with extra-hippocampal anatomical variations. The presence of IHI was assessed on T1-weighted anatomical magnetic resonance imaging (MRI) using visual criteria. We assessed the association of IHI with other anatomical changes throughout the brain using automatic morphometry of cortical sulci. We found that IHI were much more frequent in the left hippocampus (left: 17%, right: 6%, $\chi$2 - test, p < 10-28). Compared to subjects without IHI, subjects with IHI displayed morphological changes in several sulci located mainly in the limbic lobe. Our results demonstrate that IHI are a common left-sided phenomenon in normal subjects and that they are associated with morphological changes outside the medial temporal lobe.

Dell'Acqua, F., Khan, W., Gottlieb, N., Giampietro, V., …, Nees, F., …, & Simmons, A. (2015). Tract based spatial statistic reveals no differences in white matter microstructural organization between carriers and non-carriers of the APOE ε4 and ε2 alleles in young healthy adolescents. J. Alzheimer's Dis., 47(4), 977–984. PMID:26401776, doi:10.3233/JAD-140519.

The apolipoprotein E (APOE) $\epsilon$4 allele is the best established genetic risk factor for Alzheimer's disease (AD) and has been previously associated with alterations in structural gray matter and changes in functional brain activity in healthy middle-aged individuals and older non-demented subjects. In order to determine the neural mechanism by which APOE polymorphisms affect white matter (WM) structure, we investigated the diffusion characteristics of WM tracts in carriers and non-carriers of the APOE $\epsilon$4 and $\epsilon$2 alleles using an unbiased whole brain analysis technique (Tract Based Spatial Statistics) in a healthy young adolescent (14 years) cohort. A large sample of healthy young adolescents (n = 575) were selected from the European neuro imaging-genetics IMAGEN study with available APOE status and accompanying diffusion imaging data. MR Diffusion data was acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW volumes (b-value = 1,300 s/mm2 and isotropic resolution of 2.4×2.4×2.4 mm). No significant differences in WM structure were found in diffusion indices between carriers and non-carriers of the APOE $\epsilon$4 and $\epsilon$2 alleles, and dose-dependent effects of these variants were not established, suggesting that differences in WM structure are not modulated by the APOE polymorphism. In conclusion, our results suggest that microstructural properties of WM structure are not associated with the APOE $\epsilon$4 and $\epsilon$2 alleles in young adolescence, suggesting that the neural effects of these variants are not evident in 14-year-olds and may only develop later in life.

Desrivières, S., Lourdusamy, A., Tao, C., Toro, R., …, Nees, F., …, & Schumann, G. (2015). Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents. Mol. Psychiatry, 20(2), 263–274. PMID:24514566, doi:10.1038/mp.2013.197.

Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54 837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10-7), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.

Domsch, S., Zapp, J., Schad, L. R., Nees, F., …, & Vollstädt-Klein, S. (2015). Optimized protocol for high resolution functional magnetic resonance imaging at 3T using single-shot echo planar imaging. J. Neurosci. Methods, 239, 170–182. PMID:25445785, doi:10.1016/j.jneumeth.2014.10.014.

Background: To translate highly accelerated EPI-fMRI protocols as commonly used at ultra-high field strengths to clinical 3. T settings. New method: EPI protocols with increasing matrix sizes and parallel imaging (PI) factors were tested in two separate fMRI studies, a simple motor-task and a complex motivation-task experiment with focus on the sensorimotor cortex (SMC) and the nucleus accumbens (NAcc), respectively. Results: By increasing the matrix size and the PI-factor simultaneously, BOLD-sensitivity in terms of maximal t-values and numbers of activated clusters was uncompromised in single individuals in both fMRI experiments. In the SMC, the multi-subject analysis revealed an increase of 66% of the maximal t-value whereby the number of activated clusters was increased by a factor of 3.3 when the matrix size (PI-factor) was increased from 96. ×. 96 (R = 2) to 192. ×. 192 (R = 4). In the NAcc, the number of activated clusters increased from 5 to 7 whereby the maximal t-value remained unaffected when the matrix size (PI-factor) was increased from 96. ×. 96 (R = 2) to 160. ×. 160 (R = 3). Comparison with existing method: Using the proposed high-resolution EPI protocol, spatial blurring was clearly reduced. Further, BOLD sensitivity was clearly improved in multi-subject analyses and remained unaffected in single individuals compared to using the standard protocols. Conclusions: Conventionally used matrix sizes (PI-factors) might be non-optimal for some applications sacrificing BOLD spatial specificity. We recommend using the proposed high-resolution protocols applicable in detecting robust BOLD activation in fMRI.

French, L., Gray, C., Leonard, G., Perron, M., …, Nees, F., …, & Paus, T. (2015). Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence. JAMA Psychiatry, 72(10), 1002. PMID:26308966, doi:10.1001/jamapsychiatry.2015.1131.

IMPORTANCE Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure. OBJECTIVE To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014. MAIN OUTCOMES AND MEASURES Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score. RESULTS Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-{\{a}}-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-{\{a}}-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = -2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95%CI, 0.01-0.12]; P = .02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 [95%CI, 0.03-0.18]; P = .004). CONCLUSIONS AND RELEVANCE Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.

Fritsch, V., Da Mota, B., Loth, E., Varoquaux, G., …, Nees, F., …, & Thirion, B. (2015). Robust regression for large-scale neuroimaging studies. Neuroimage, 111, 431–441. PMID:25731989, doi:10.1016/j.neuroimage.2015.02.048.

Multi-subject datasets used in neuroimaging group studies have a complex structure, as they exhibit non-stationary statistical properties across regions and display various artifacts.While studies with small sample sizes can rarely be shown to deviate from standard hypotheses (such as the normality of the residuals) due to the poor sensitivity of normality tests with low degrees of freedom, large-scale studies (e.g. >. 100 subjects) exhibit more obvious deviations from these hypotheses and call for more refined models for statistical inference. Here, we demonstrate the benefits of robust regression as a tool for analyzing large neuroimaging cohorts. First, we use an analytic test based on robust parameter estimates; based on simulations, this procedure is shown to provide an accurate statistical control without resorting to permutations. Second, we show that robust regression yields more detections than standard algorithms using as an example an imaging genetics study with 392 subjects. Third, we show that robust regression can avoid false positives in a large-scale analysis of brain-behavior relationships with over 1500 subjects. Finally we embed robust regression in the Randomized Parcellation Based Inference (RPBI) method and demonstrate that this combination further improves the sensitivity of tests carried out across the whole brain. Altogether, our results show that robust procedures provide important advantages in large-scale neuroimaging group studies.

Galinowski, A., Miranda, R., Lemaître, H., Paillère-Martinot, M. L., …, Nees, F., …, & Martinot, J.-L. (2015). Resilience and corpus callosum microstructure in adolescence. Psychol. Med., 45(11), 2285–2294. PMID:25817177, doi:10.1017/S0033291715000239.

Background Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. Method Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. Results Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. Conclusion High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

Griebe, M.*, Nees, F.*, Gerber, B., Ebert, A., …, & Szabo, K. (2015). Stronger Pharmacological Cortisol Suppression and Anticipatory Cortisol Stress Response in Transient Global Amnesia. Front. Behav. Neurosci., 9(March), 1–8. doi:10.3389/fnbeh.2015.00063.

Transient global amnesia (TGA) is a disorder characterized by a sudden attack of severe anterograde memory disturbance that is frequently preceded by emotional or physical stress and resolves within 24 h. By using MRI following the acute episode in TGA patients, small lesions in the hippocampus have been observed. Hence, it has been hypothesized that the disorder is caused by a stress-related transient inhibition of memory formation in the hippocampus. To study the factors that may link stress and TGA, we measured the cortisol day-profile, the dexamethasone feedback inhibition and the effect of experimental exposure to stress on cortisol levels (using the socially evaluated cold pressor test and a control procedure) in 20 patients with a recent history of TGA and in 20 healthy controls. We used self-report scales of depression, anxiety and stress, and a detailed neuropsychological assessment to characterize our collective. We did not observe differences in mean cortisol levels in the cortisol day-profile between the two groups. After administration of low-dose dexamethasone, TGA patients showed significantly stronger cortisol suppression in the daytime profile compared to the control group (p = 0.027). The mean salivary cortisol level was significantly higher in the TGA group prior to and after the experimental stress exposure (p = 0.008 and 0.010 respectively), as well as prior to and after the control condition (p = 0.022 and 0.024, respectively). The TGA group had higher scores of depressive symptomatology (p = 0.021) and anxiety (p = 0.007), but the groups did not differ in the neuropsychological assessment. Our findings of a stronger pharmacological suppression and higher cortisol levels in anticipation of experimental stress in participants with a previous TGA indicate a hypersensitivity of the HPA axis. This suggests that an individual stress sensitivity might play a role in the pathophysiology of TGA.

Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., …, IMAGEN Consortium, & Medland, S. E. (2015). Common genetic variants influence human subcortical brain structures. Nature, 520(7546), 224–229. doi:10.1038/nature14101.
Jurk, S., Kuitunen-Paul, S., Kroemer, N. B., Artiges, E., …, Nees, F., …, & Smolka, M. N. (2015). Personality and Substance Use: Psychometric Evaluation and Validation of the Substance Use Risk Profile Scale (SURPS) in English, Irish, French, and German Adolescents. Alcohol. Clin. Exp. Res., 39(11), 2234–2248. PMID:26463560, doi:10.1111/acer.12886.

Background: The aim of the present longitudinal study was the psychometric evaluation of the Substance Use Risk Profile Scale (SURPS). Methods: We analyzed data from N = 2,022 adolescents aged 13 to 15 at baseline assessment and 2 years later (mean interval 2.11 years). Missing data at follow-up were imputed (N = 522). Psychometric properties of the SURPS were analyzed using confirmatory factor analysis. We examined structural as well as convergent validity with other personality measurements and drinking motives, and predictive validity for substance use at follow-up. Results: The hypothesized 4-factorial structure (i.e., anxiety sensitivity, hopelessness, impulsivity [IMP], and sensation seeking [SS]) based on all 23 items resulted in acceptable fit to empirical data, acceptable internal consistencies, low to moderate test-retest reliability coefficients, as well as evidence for factorial and convergent validity. The proposed factor structure was stable for both males and females and, to lesser degree, across languages. However, only the SS and the IMP subscales of the SURPS predicted substance use outcomes at 16 years of age. Conclusions: The SURPS is unique in its specific assessment of traits related to substance use disorders as well as the resulting shortened administration time. Test-retest reliability was low to moderate and comparable to other personality scales. However, its relation to future substance use was limited to the SS and IMP subscales, which may be due to the relatively low-risk substance use pattern in the present sample.

Müller, K. U., Gan, G., Banaschewski, T., Barker, G. J., …, Nees, F., …, & Smolka, M. N. (2015). No differences in ventral striatum responsivity between adolescents with a positive family history of alcoholism and controls. Addict. Biol., 20(3), 534–545. PMID:24903627, doi:10.1111/adb.12136.

Individuals with alcohol-dependent parents show an elevated risk of developing alcohol-related problems themselves. Modulations of the mesolimbic reward circuit have been postulated as a pre-existing marker of alcoholism. We tested whether a positive family history of alcoholism is correlated with ventral striatum functionality during a reward task. All participants performed a modified version of the monetary incentive delay task while their brain responses were measured with functional magnetic resonance imaging. We compared 206 healthy adolescents (aged 13-15) who had any first- or second-degree relative with alcoholism to 206 matched controls with no biological relative with alcoholism. Reward anticipation as well as feedback of win recruited the ventral striatum in all participants, but adolescents with a positive family history of alcoholism did not differ from their matched peers. Also we did not find any correlation between family history density and reward anticipation or feedback of win. This finding of no differences did not change when we analyzed a subsample of 77 adolescents with at least one parent with alcohol use disorder and their matched controls. Because this result is in line with another study reporting no differences between children with alcohol-dependent parents and controls at young age, but contrasts with studies of older individuals, one might conclude that at younger age the effect of family history has not yet exerted its influence on the still developing mesolimbic reward circuit.

Nees, F., Heinrich, A., & Flor, H. (2015). A mechanism-oriented approach to psychopathology: The role of Pavlovian conditioning. Int. J. Psychophysiol., 98(2), 351–364. PMID:25979157, doi:10.1016/j.ijpsycho.2015.05.005.

The Research Domain Criteria Project suggests to base the classification of mental disorders on dimensions of observable behavior and neurobiological measures of these functions rather than on symptom-based descriptive categorical diagnoses. We suggest a mechanistic approach that focuses on the role of learning as a core mechanism that can be studied in animals and humans. We review human studies on neurobiological, psychophysiological, and behavioral correlates of Pavlovian associative learning and delineate commonalities and differences across disorders. In addition to the hedonic value, the learning phase (i.e. habituation, acquisition, extinction, extinction recall), the role of stimulus properties (i.e., cue and context), and event timing (e.g. delay and trace conditioning) were considered. We address how core behavioral and psychophysiological indicators of conditioning, such as contingency ratings and skin conductance responses or startle modulation, respectively, are altered. We also discuss plastic changes in core brain regions and the interaction of brain regions in inhibitory and excitatory circuits. We also address the translation of findings pertaining to classical conditioning and its affiliated processes into the development of new behavioral and pharmacological treatments for mental disorders, and discuss productive avenues for future studies.

Nees, F. (2015). The nicotinic cholinergic system function in the human brain. Neuropharmacology, 96(PB), 289–301. PMID:25446570, doi:10.1016/j.neuropharm.2014.10.021.

Abstract Research on the nicotinic cholinergic system function in the brain was previously mainly derived from animal studies, yet, research in humans is growing. Up to date, findings allow significant advances on the understanding of nicotinic cholinergic effects on human cognition, emotion and behavior using a range of functional brain imaging approaches such as pharmacological functional magnetic resonance imaging or positron emission tomography. Studies provided insights across various mechanistic psychological domains using different tasks as well as at rest in both healthy individuals and patient populations, with so far partly mixed results reporting both enhancements and decrements of neural activity related to the nicotinic cholinergic system. Moreover, studies on the relation between brain structure and the nicotinic cholinergic system add important information in this context. The present review summarizes the current status of human brain imaging studies and presents the findings within a theoretical and clinical perspective as they may be useful not only for an advancement of the understanding of basic nicotinic cholinergic-related mechanisms, but also for the development and integration of psychological and pharmacological treatment approaches. Patterns of functional neuroanatomy and neural circuitry across various cognitive and emotional domains may be used as neuropsychological markers of mental disorders such as addiction, Alzheimer's disease, Parkinson disease or schizophrenia, where nicotinic cholinergic system changes are characteristic. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

Nees, F., Witt, S. H., Dinu-Biringer, R., Lourdusamy, A., …, & Flor, H. (2015). BDNF Val66Met and reward-related brain function in adolescents: role for early alcohol consumption. Alcohol, 49(2), 103–110. PMID:25650137, doi:10.1016/j.alcohol.2014.12.004.

Changes in reward processing have been identified as one important pathogenetic mechanism in alcohol addiction. The nonsynonymous single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (rs6265/Val66Met) modulates the central nervous system activity of neurotransmitters involved in reward processing such as serotonin, dopamine, and glutamate. It was identified as crucial for alcohol consumption in healthy adults and, in rats, specifically related to the function in the striatum, a region that is commonly involved in reward processing. However, studies in humans on the association of BDNF Val66Met and reward-related brain functions and its role for alcohol consumption, a significant predictor of later alcohol addiction, are missing. Based on an intermediate phenotype approach, we assessed the early orientation toward alcohol and alcohol consumption in 530 healthy adolescents that underwent a monetary incentive delay task during functional magnetic resonance imaging. We found a significantly lower response in the putamen to reward anticipation in adolescent Met carriers with high versus low levels of alcohol consumption. During reward feedback, Met carriers with low putamen reactivity were significantly more likely to orient toward alcohol and to drink alcohol 2 years later. This study indicates a possible effect of BDNF Val66Met on alcohol addiction-related phenotypes in adolescence.

O'Leary-Barrett, M., Pihl, R. O., Artiges, E., Banaschewski, T., …, Nees, F., …, & Rogers, J. (2015). Personality, Attentional Biases towards Emotional Faces and Symptoms of Mental Disorders in an Adolescent Sample. PLoS One, 10(6), e0128271. PMID:26046352, doi:10.1371/journal.pone.0128271.

Objective: To investigate the role of personality factors and attentional biases towards emotional faces, in establishing concurrent and prospective risk for mental disorder diagnosis in adolescence. Method: Data were obtained as part of the IMAGEN study, conducted across 8 European sites, with a community sample of 2257 adolescents. At 14 years, participants completed an emotional variant of the dot-probe task, as well two personality measures, namely the Substance Use Risk Profile Scale and the revised NEO Personality Inventory. At 14 and 16 years, participants and their parents were interviewed to determine symptoms of mental disorders. Results: Personality traits were general and specific risk indicators for mental disorders at 14 years. Increased specificity was obtained when investigating the likelihood of mental disorders over a 2-year period, with the Substance Use Risk Profile Scale showing incremental validity over the NEO Personality Inventory. Attentional biases to emotional faces did not characterise or predict mental disorders examined in the current sample. Discussion: Personality traits can indicate concurrent and prospective risk for mental disorders in a community youth sample, and identify at-risk youth beyond the impact of baseline symptoms. This study does not support the hypothesis that attentional biases mediate the relationship between personality and psychopathology in a community sample. Task and sample characteristics that contribute to differing results among studies are discussed.

Ojelade, S. A., Jia, T., Rodan, A. R., Chenyang, T., …, IMAGEN Consortium, & Rothenfluh, A. (2015). Rsu1 regulates ethanol consumption in Drosophila and humans. Proc. Natl. Acad. Sci., 112(30), E4085—-E4093. PMID:26170296, doi:10.1073/pnas.1417222112.

Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high na{\"{i}}ve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal na{\"{i}}ve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate na{\"{i}}ve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.

Ortuño-Sierra, J., Fonseca-Pedrero, E., Aritio-Solana, R., Velasco, A. M., …, Nees, F., …, & Lawrence, C. (2015). New evidence of factor structure and measurement invariance of the SDQ across five European nations. Eur. Child Adolesc. Psychiatry, 24(12), 1523–1534. PMID:26036862, doi:10.1007/s00787-015-0729-x.

The main purpose of the present study was to analyse the internal structure and to test the measurement invariance of the Strengths and Difficulties Questionnaire (SDQ), self-reported version, in five European countries. The sample consisted of 3012 adolescents aged between 12 and 17 years (M = 14.20; SD = 0.83). The five-factor model (with correlated errors added), and the five-factor model (with correlated errors added) with the reverse-worded items allowed to cross-load on the Prosocial subscale, displayed adequate goodness of-fit indices. Multi-group confirmatory factor analysis showed that the five-factor model (with correlated errors added) had partial strong measurement invariance by countries. A total of 11 of the 25 items were non-invariant across samples. The level of internal consistency of the Total difficulties score was 0.84, ranging between 0.69 and 0.78 for the SDQ subscales. The findings indicate that the SDQ's subscales need to be modified in various ways for screening emotional and behavioural problems in the five European countries that were analysed.

Pohlack, S. T., Nees, F., Ruttorf, M., Cacciaglia, R., …, & Flor, H. (2015). Neural Mechanism of a Sex-Specific Risk Variant for Posttraumatic Stress Disorder in the Type i Receptor of the Pituitary Adenylate Cyclase Activating Polypeptide. Biol. Psychiatry, 78(12), 840–847. PMID:25680674, doi:10.1016/j.biopsych.2014.12.018.

Background Posttraumatic stress disorder (PTSD) is a frequent anxiety disorder with higher prevalence rates in female patients than in male patients (2.5:1). Association with a single nucleotide polymorphism (rs2267735) in the gene ADCYAP1R1 encoding the type I receptor (PAC1-R) of the pituitary adenylate cyclase activating polypeptide has been reported with PTSD in female patients. We sought to identify the neural correlates of the described PAC1-R effects on associative learning. Methods In a reverse genetic approach, we examined two independent healthy samples (N1 = 112, N2 = 73) using functional magnetic resonance imaging during cued and contextual fear conditioning. Skin conductance responses and verbal self-reports of arousal, valence, and contingency were recorded. Results We found that PAC1-R modulates the blood oxygenation level-dependent response of the hippocampus. Specifically, we observed decreased hippocampal activity during contextual, but not during cued, fear conditioning in female participants carrying the PAC1-R risk allele. We observed no significant differences in conditionability for skin conductance responses, verbal reports, or activation in other brain regions between the genotype groups in female participants. Conclusions Our results suggest that impaired contextual conditioning in the hippocampal formation may mediate the association between PAC1-R and PTSD symptoms. Our findings potentially identify a missing link between the involvement of PAC1-R in PTSD and the well-established structural and functional hippocampal deficits in these patients.

Richiardi, J., Altmann, A., Milazzo, A. C., Chang, C., …, Nees, F., …, & Greicius, M. D. (2015). Correlated gene expression supports synchronous activity in brain networks. Science (80-. )., 348(6240), 1241–1244. PMID:26068849, doi:10.1126/science.1255905.

During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set. The set of 136 genes we identify is significantly enriched for ion channels. Polymorphisms in this set of genes significantly affect resting-state functional connectivity in a large sample of healthy adolescents. Expression levels of these genes are also significantly associated with axonal connectivity in the mouse. The results provide convergent, multimodal evidence that resting-state functional networks correlate with the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function.

Ruggeri, B., Nymberg, C., Vuoksimaa, E., Lourdusamy, A., …, Nees, F., …, & Schumann, G. (2015). Association of protein phosphatase PPM1G with alcohol use disorder and brain activity during behavioral control in a genome-wide methylation analysis. Am. J. Psychiatry, 172(6), 543–552. PMID:25982659, doi:10.1176/appi.ajp.2014.14030382.

Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. Results: Hypermethylation in the 3:-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1Ghypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

Spechler, P. A., Orr, C. A., Chaarani, B., Kan, K. J., …, Nees, F., …, IMAGEN Consortium, & Garavan, H. (2015). Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat. Dev. Cogn. Neurosci., 16, 63–70. PMID:26347227, doi:10.1016/j.dcn.2015.08.007.

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n = 70) of 14-year olds with a history of cannabis use to a group (n = 70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood.

Steiger, F., Nees, F., Wicking, M., Lang, S., & Flor, H. (2015). Behavioral and central correlates of contextual fear learning and contextual modulation of cued fear in posttraumatic stress disorder. Int. J. Psychophysiol., 98(3), 584–593. PMID:26149734, doi:10.1016/j.ijpsycho.2015.06.009.

Patients with posttraumatic stress disorder (PTSD) show persistent fear responses to trauma cues in contexts in which these cues no longer predict danger. This might be related to deficient context and enhanced cue conditioning. To test this hypothesis, we examined context conditioning directly followed by a cue conditioning phase against the background of the previously conditioned context in 12 patients with PTSD, 14 traumatized control subjects without PTSD and 11 matched never-traumatized controls. We used differential context and cue conditioning paradigms, with rooms as contexts and geometric figures as cues, and assessed valence, arousal and contingency ratings as well as brain responses using functional magnetic resonance imaging. The PTSD patients showed more hippocampal activation and differentiated the threat and safe contexts less in their contingency ratings than the healthy controls during context acquisition. In the subsequent cue acquisition against the background of the conditioned context, they displayed similar threat versus safe cue differentiation in contingency ratings as the two control groups. Moreover, PTSD patients failed to extinguish the differential conditioned context and cued fear responses and showed increased fear to both the dangerous and the safe conditioned contexts and cues in some ratings. This study provides evidence for a dissociation of brain responses and contingency awareness in PTSD which represents impaired context learning and a deficient contextual modulation of cue-related associations. In addition, extinction and extinction recall were impaired in PTSD. These changes were related to PTSD symptoms and suggest that contextual learning deficits may contribute to PTSD.

Stringaris, A., Belil, P. V. R., Artiges, E., Lemaître, H., …, Nees, F., …, & Rogers, J. (2015). The brain s response to reward anticipation and depression in adolescence: Dimensionality, specificity, and longitudinal predictions in a community-based sample. Am. J. Psychiatry, 172(12), 1215–1223. PMID:26085042, doi:10.1176/appi.ajp.2015.14101298.

Toro, R., Poline, J.-B., Huguet, G., Loth, E., …, Nees, F., …, & Bourgeron, T. (2015). Genomic architecture of human neuroanatomical diversity. Mol. Psychiatry, 20(8), 1011–1016. PMID:25224261, doi:10.1038/mp.2014.99.

Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.

Vulser, H., Lemaître, H., Artiges, E., Miranda, R., …, Nees, F., …, & Stephens, D. (2015). Subthreshold Depression and Regional Brain Volumes in Young Community Adolescents. J. Am. Acad. Child Adolesc. Psychiatry, 54(10), 832–840. PMID:26407493, doi:10.1016/j.jaac.2015.07.006.

Objective Neuroimaging findings have been reported in regions of the brain associated with emotion in both adults and adolescents with depression, but few studies have investigated whether such brain alterations can be detected in adolescents with subthreshold depression, a condition at risk for major depressive disorder. In this study, we searched for differences in brain structure at age 14 years in adolescents with subthreshold depression and their relation to depression at age 16 years. Method High-resolution structural magnetic resonance imaging was used to assess adolescents with self-reported subthreshold depression (n = 119) and healthy control adolescents (n = 461), all recruited from a community-based sample. Regional gray and white matter volumes were compared across groups using whole-brain voxel-based morphometry. The relationship between subthreshold depression at baseline and depression outcome was explored using causal mediation analyses to search for mediating effects of regional brain volumes. Results Adolescents with subthreshold depression had smaller gray matter volume in the ventromedial prefrontal and rostral anterior cingulate cortices and caudates, and smaller white matter volumes in the anterior limb of internal capsules, left forceps minor, and right cingulum. In girls, but not in boys, the relation between subthreshold depression at baseline and high depression score at follow-up was mediated by medial-prefrontal gray matter volume. Conclusion Subthreshold depression in early adolescence might be associated with smaller gray and white matter volumes in regions of the frontal-striatal-limbic affective circuit, and the occurrence of depression in girls with subthreshold depression might be influenced by medial-prefrontal gray matter volume. However, these findings should be interpreted with caution because of the limitations of the clinical assessment methods.

#### 2014

Castellanos-Ryan, N., Struve, M., Whelan, R., Banaschewski, T., …, Nees, F., …, & Conrod, P. J. (2014). Neural and cognitive correlates of the common and specific variance across externalizing problems in young adolescence. Am. J. Psychiatry, 171(12), 1310–1319. PMID:25073448, doi:10.1176/appi.ajp.2014.13111499.

Objective: The authors sought to model the unique and common variance across conduct disorder, substancemisuse, and attention deficit hyperactivity disorder (ADHD) and to investigate the neurocognitive factors that relate generally or uniquely to externalizing problems in adolescence. Method: Personality and behavioralmeasures and functional imaging responses to reward sensitivity and response inhibition tasks were assessed in 1,778 European adolescents at age 14 and, using structural equation modeling, were related to the unique and common variance across externalizing problems assessed and modeled at ages 14 and 16. Results: Externalizing problems best fit a general-specific model made up of a specific factor representing ADHD and conduct disorder symptoms, a specific factor representing substance misuse symptoms, and a common externalizing factor representing the variance shared among all symptoms. Common variance across externalizing problems was associated with high impulsivity and delay discounting as well as low blood-oxygen-level-dependent (BOLD) response in the substantia nigra and subthalamic nucleus but high BOLD response in the presupplementary motor area and precentral gyrus during successful inhibition. Unique variance for ADHD/ conduct disorder was associated with impulsivity, poor response inhibition, and high delay discounting, aswell as low BOLD response in frontal brain areas bilaterally during failed inhibition. In contrast, unique variance for substance misuse was associated with high sensation seeking and delay discounting, as well as differential brain response to reward anticipation: High BOLD response in the left orbitofrontal cortex but low BOLD response in the left inferior frontal gyrus. Conclusions: Personality, behavioral, and fMRI findings suggest that abnormalities in response inhibition, error processing, and reward processing are differentially implicated in underlying vulnerability specific to ADHD/conduct disorder and substance misuse and general to externalizing problems.

Da Mota, B., Fritsch, V., Varoquaux, G., Banaschewski, T., …, Nees, F., …, & Thirion, B. (2014). Randomized parcellation based inference. Neuroimage, 89, 203–215. PMID:24262376, doi:10.1016/j.neuroimage.2013.11.012.

Neuroimaging group analyses are used to relate inter-subject signal differences observed in brain imaging with behavioral or genetic variables and to assess risks factors of brain diseases. The lack of stability and of sensitivity of current voxel-based analysis schemes may however lead to non-reproducible results. We introduce a new approach to overcome the limitations of standard methods, in which active voxels are detected according to a consensus on several random parcellations of the brain images, while a permutation test controls the false positive risk. Both on synthetic and real data, this approach shows higher sensitivity, better accuracy and higher reproducibility than state-of-the-art methods. In a neuroimaging-genetic application, we find that it succeeds in detecting a significant association between a genetic variant next to the COMT gene and the BOLD signal in the left thalamus for a functional Magnetic Resonance Imaging contrast associated with incorrect responses of the subjects from a Stop Signal Task protocol. {\textcopyright}2013 Elsevier Inc.

Davids, M., Zöllner, F. G., Ruttorf, M., Nees, F., …, & Schad, L. R. (2014). Fully-automated quality assurance in multi-center studies using MRI phantom measurements. Magn. Reson. Imaging, 32(6), 771–780. PMID:24602825, doi:10.1016/j.mri.2014.01.017.

Phantom measurements allow for investigating the overall quality characteristics of an MRI scanner. Especially within multicenter studies, these characteristics ensure the comparability of the results across different sites, in addition to the performance stability of a single scanner over time. This comparability requires consistent phantoms, sequence protocols, and quality assurance criteria. Within the scope of this work, a software library was implemented for fully-automated determination of important quality characteristics (comprising signal-to-noise ratio, image uniformity, ghosting artifacts, chemical shift and spatial resolution and linearity) including methods for data preparation, automated pre- and postprocessing as well as visualization and interpretation. All methods were evaluated using both synthetic images with predefined distortions and a set of 44 real phantom measurements involving eight sites and three manufacturers. Using the synthetic phantom images, predefined levels of distortion that were incorporated artificially were correctly detected by the automated routines with no more than 2.6% of relative error. In addition, the methods were applied to real phantom measurements - all data sets could be evaluated automatically considering all quality parameters as long as the acquisition protocols are followed. Shortcomings of the processability only occurred in the ghosting artifacts (39/44 evaluable) and the spatial linearity (43/44 evaluable) analysis due to gross misalignments of the phantom during image acquisition. Based on evaluation results, the accuracy of the evaluation appears to be robust to misalignments, artifacts, and distortions affecting the images, allowing for objective fully-automated evaluation and interpretation of large data set numbers. {\textcopyright}2014 Elsevier Inc.

Dickie, E. W., Tahmasebi, A. M., French, L., Kovacevic, N., …, Nees, F., …, & Paus, T. (2014). Global Genetic Variations Predict Brain Response to Faces. PLoS Genet., 10(8), e1004523. PMID:25122193, doi:10.1371/journal.pgen.1004523.

Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40–50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R2 = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R2 = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.

Flor, H., & Nees, F. (2014). Learning, memory and brain plasticity in posttraumatic stress disorder: Context matters. Restor. Neurol. Neurosci., 32(1), 95–102. PMID:23945193, doi:10.3233/RNN-139013.

We review evidence from our laboratory that suggests that in addition to enhanced cue conditioning and delayed cue extinction disturbed contextual learning may play an important role in the development and maintenance of posttraumatic stress disorder. Based on data from a longitudinal sample of rescue workers at high risk for posttraumatic stress disorder and data on single trauma exposed persons with and without posttraumatic stress disorder we show the crucial role of the hippocampus for contextual memory and impaired contextual learning along with enhanced cue conditioning and delayed extinction in PTSD. Using structural and functional magnetic resonance imaging we confirmed animal data on the role of the hippocampus in contextual and the importance of the amygdala in cue conditioning and the role of the frontal cortex in extinction. Genetic variants related to the modulation of the hypothalamus-pituitary-adrenal axis are associated with cue and genetic variants related to calcium signaling and memory processes and the regulation of the stress response are associated with context conditioning. These genes also play a role in PTSD. Further research needs to identify the predictive nature of these learning processes and plastic brain changes and their interaction with genetic characteristics changes for the transition into PTSD and its maintenance. A further focus needs to be on the identification of learning and memory mechanisms and the associated brain plasticity across disorders. {\textcopyright}2014 - IOS Press and the authors. All rights reserved.

Heinrich, A., Szostek, A., Meyer, P., Reinhard, I., …, & Nees, F. (2014). Women are more strongly affected by dizziness in static magnetic fields of magnetic resonance imaging scanners. Neuroreport, 25(14), 1081–1084. PMID:25089803, doi:10.1097/WNR.0000000000000225.

Increasing field strengths in MRI necessitate the examination of potential side effects. Previously reported results have been contradictory, possibly caused by imbalanced samples. We aimed to examine whether special groups of people are more prone to develop side effects that might have led to contradictory results in previous studies. We examined the occurrence of sensory side effects in static magnetic fields of MRI scanners of 1.5, 3, and 7 T and a mock scanner in 41 healthy participants. The contribution of field strength, sex, age, and attention to bodily processes, and stress hormone levels to the sensation of dizziness was examined in separate univariate analyses and in a joint analysis that included all variables. Field strength and sex were significant factors in the joint analysis (P=0.001), with women being more strongly affected than men by dizziness in higher static magnetic fields. This effect was not mediated by the other variables such as attention to bodily symptoms or stress hormones. Further research needs to elucidate the underlying factors of increased dizziness in women in static magnetic fields in MRI. We hypothesize that imbalanced samples of earlier studies might be one reason for previous contradictory results on the side effects of static magnetic fields.

Khan, W., Giampietro, V., Ginestet, C., Dell'Acqua, F., …, Nees, F., …, & Simmons, A. (2014). No differences in hippocampal volume between carriers and non-carriers of the ApoE ε4 and ε2 alleles in young healthy adolescents. J. Alzheimer's Dis., 40(1), 37–43. PMID:24326516, doi:10.3233/JAD-131841.

Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimer's disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE $\epsilon$4 or $\epsilon$2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these polymorphisms may only become apparent in later life. {\textcopyright}2014 - IOS Press and the authors. All rights reserved.

Kühn, S., Lorenz, R., Banaschewski, T., Barker, G. J., …, Nees, F., …, & Gallinat, J. (2014). Positive association of video game playing with left frontal cortical thickness in adolescents. PLoS One, 9(3), 5–10. PMID:24633348, doi:10.1371/journal.pone.0091506.

Playing video games is a common recreational activity of adolescents. Recent research associated frequent video game playing with improvements in cognitive functions. Improvements in cognition have been related to grey matter changes in prefrontal cortex. However, a fine-grained analysis of human brain structure in relation to video gaming is lacking. In magnetic resonance imaging scans of 152 14-year old adolescents, FreeSurfer was used to estimate cortical thickness. Cortical thickness across the whole cortical surface was correlated with self-reported duration of video gaming (hours per week). A robust positive association between cortical thickness and video gaming duration was observed in left dorsolateral prefrontal cortex (DLPFC) and left frontal eye fields (FEFs). No regions showed cortical thinning in association with video gaming frequency. DLPFC is the core correlate of executive control and strategic planning which in turn are essential cognitive domains for successful video gaming. The FEFs are a key region involved in visuo-motor integration important for programming and execution of eye movements and allocation of visuo-spatial attention, processes engaged extensively in video games. The results may represent the biological basis of previously reported cognitive improvements due to video game play. Whether or not these results represent a-priori characteristics or consequences of video gaming should be studied in future longitudinal investigations. {\textcopyright}2014 K{\"{u}}hn et al.

Loth, E., Poline, J.-B., Thyreau, B., Jia, T., …, Nees, F., …, & Schumann, G. (2014). Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events. Biol. Psychiatry, 76(5), 367–376. PMID:24120094, doi:10.1016/j.biopsych.2013.07.043.

Background Common variants in the oxytocin receptor gene (OXTR) have been shown to influence social and affective behavior and to moderate the effect of adverse experiences on risk for social-affective problems. However, the intermediate neurobiological mechanisms are not fully understood. Although human functional neuroimaging studies have reported that oxytocin effects on social behavior and emotional states are mediated by amygdala function, animal models indicate that oxytocin receptors in the ventral striatum (VS) modulate sensitivity to social reinforcers. This study aimed to comprehensively investigate OXTR-dependent brain mechanisms associated with social-affective problems. Methods In a sample of 1445 adolescents we tested the effect of 23-tagging single nucleotide polymorphisms across the OXTR region and stressful life events (SLEs) on functional magnetic resonance imaging blood oxygen level-dependent activity in the VS and amygdala to animated angry faces. Single nucleotide polymorphisms for which gene-wide significant effects on brain function were found were then carried forward to examine associations with social-affective problems. Results A gene-wide significant effect of rs237915 showed that adolescents with minor CC-genotype had significantly lower VS activity than CT/TT-carriers. Significant or nominally significant gene × environment effects on emotional problems (in girls) and peer problems (in boys) revealed a strong increase in clinical symptoms as a function of SLEs in CT/TT-carriers but not CC-homozygotes. However, in low-SLE environments, CC-homozygotes had more emotional problems (girls) and peer problems (boys). Moreover, among CC-homozygotes, reduced VS activity was related to more peer problems. Conclusions These findings suggest that a common OXTR-variant affects brain responsiveness to negative social cues and that in "risk- carriers" reduced sensitivity is simultaneously associated with more social-affective problems in "favorable environments" and greater resilience against stressful experiences. {\textcopyright}2014 Society of Biological Psychiatry.

Marečková, K., Perrin, J. S., Nawaz Khan, I., Lawrence, C., …, IMAGEN Consortium, & Khan, I. N. (2014). Hormonal contraceptives, menstrual cycle and brain response to faces. Soc. Cogn. Affect. Neurosci., 9(2), 191–200. PMID:23175677, doi:10.1093/scan/nss128.

Both behavioral and neuroimaging evidence support a female advantage in the perception of human faces. Here we explored the possibility that this relationship may be partially mediated by female sex hormones by investigating the relationship between the brain's response to faces and the use of oral contraceptives, as well as the phase of the menstrual cycle. First, functional magnetic resonance images were acquired in 20 young women [10 freely cycling and 10 taking oral contraception (OC)] during two phases of their cycle: mid-cycle and menstruation. We found stronger neural responses to faces in the right fusiform face area (FFA) in women taking oral contraceptives (vs freely cycling women) and during mid-cycle (vs menstruation) in both groups. Mean blood oxygenation level-dependent response in both left and right FFA increased as function of the duration of OC use. Next, this relationship between the use of OC and FFA response was replicated in an independent sample of 110 adolescent girls. Finally in a parallel behavioral study carried out in another sample of women, we found no evidence of differences in the pattern of eye movements while viewing faces between freely cycling women vs those taking oral contraceptives. The imaging findings might indicate enhanced processing of social cues in women taking OC and women during mid-cycle.

Nees, F., & Pohlack, S. T. (2014). Functional MRI studies of the hippocampus. Hippocampus Clin. Neurosci., 34, 85–94. PMID:24777133, doi:10.1159/000356427.

Developments in tasks and imaging techniques applied over the last decades have yielded substantial support for the hypothesized role of the hippocampus in mnemonic processes. Human imaging research has now moved on to disentangle the contributions of the different hippocampal subregions and adjacent cortices, so as to bridge the gap between rodent and human data. Besides the importance of such studies for basic research, the investigation of hippocampal (dys)function has clinical relevance for diseases ranging from neurological disorders such as Alzheimer's disease or epilepsy to mental disorders such as schizophrenia or anxiety disorders. So far, most of the present review articles and books about the hippocampus and its functions focus on traditional declarative memory paradigms and 'encoding versus retrieval'. In this chapter we concentrate on a less travelled, but not less important, route concerning the role of the hippocampus in a well-established associative learning (encoding) paradigm: pavlovian fear conditioning. Fear conditioning is hypothesized to model aversive associative learning on a nonpathological level and is further assumed to recruit the same networks that are relevant for anxiety disorders, with the hippocampus being specific for contextual fear conditioning. We highlight the findings in humans by addressing its role in mediating spatial and temporal aspects of a context, involving different kinds of a fear-conditioning procedure (delay vs. trace conditioning), and its role in extinction, both from a theoretical and clinical perspective.

Nees, F.*, & Flor, H.*. (2014). Neuroanatomy and Neuroimaging. Wiley Handb. Anxiety Disord. (pp. 233–253). Chichester, UK: John Wiley & Sons, Ltd.
Nymberg, C., Banaschewski, T., Bokde, A. L. W., Büchel, C., …, Nees, F., …, & Rogers, J. (2014). DRD2/ANKK1 polymorphism modulates the effect of ventral striatal activation on working memory performance. Neuropsychopharmacology, 39(10), 2357–2365. PMID:24713612, doi:10.1038/npp.2014.83.

Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13-15 years) and BrainChild (n∼300, age 6-27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission. {\textcopyright}2014 American College of Neuropsychopharmacology.

Paillère-Martinot, M. L., Lemaître, H., Artiges, E., Miranda, R., …, IMAGEN Consortium, & Martinot, J.-L. (2014). White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms. Mol. Psychiatry, 19(4), 462–470. PMID:23628983, doi:10.1038/mp.2013.44.

Rance, M., Ruttorf, M., Nees, F., Schad, L. R., & Flor, H. (2014). Neurofeedback of the difference in activation of the anterior cingulate cortex and posterior insular cortex: Two functionally connected areas in the processing of pain. Front. Behav. Neurosci., 8(OCT), 1–12. doi:10.3389/fnbeh.2014.00357.

The aim of this study was the analysis of the effect of a learned increase in the dissociation between the rostral anterior cingulate cortex (rACC) and the left posterior insula (pInsL) on pain intensity and unpleasantness and the contribution of each region to the effect, exploring the possibility to influence the perception of pain with neurofeedback methods. We trained ten healthy subjects to increase the difference in the blood oxygenation level-dependent response between the rACC and pInsL to painful electric stimuli. Subjects learned to increase the dissociation with either the rACC (state 1) or the pInsL (state 2) being higher. For feedback we subtracted the signal of one region from the other and provided feedback in four conditions with six trials each yielding two different states: [rACC—pInsL increase (state 1), rACC—pInsL decrease (state 2), pInsL—rACC increase (state 2), pInsL—rACC decrease (state 1)]. Significant changes in the dissociation from trial one to six were seen in all conditions. There were significant changes from trial one to six in the pInsL in three of the four conditions, the rACC showed no significant change. Pain intensity or unpleasantness ratings were unrelated to the dissociation between the regions and the activation in each region. Learning success in the conditions did not significantly correlate and there was no significant correlation between the two respective conditions of one state, i.e., learning to achieve a specific state is not a stable ability. The pInsL seems to be the driving force behind changes in the learned dissociation between the regions. Despite successful differential modulation of activation in areas responsive to the painful stimulus, no corresponding changes in the perception of pain intensity or unpleasantness emerged. Learning to induce different states of dissociation between the areas is not a stable ability since success did not correlate overall or between two conditions of the the same state.

Rance, M., Ruttorf, M., Nees, F., Schad, L. R., & Flor, H. (2014). Real time fMRI feedback of the anterior cingulate and posterior insular cortex in the processing of pain. Hum. Brain Mapp., 35(12), 5784–5798. PMID:25045017, doi:10.1002/hbm.22585.

Self-regulation of brain activation using real-time functional magnetic resonance imaging has been used to train subjects to modulate activation in various brain areas and has been associated with behavioral changes such as altered pain perception. The aim of this study was to assess the comparability of upregulation versus downregulation of activation in the rostral anterior cingulate cortex (rACC) and left posterior insula (pInsL) and its effect on pain intensity and unpleasantness. In a first study, we trained 10 healthy subjects to separately upregulate and downregulate the blood oxygenation level-dependent response in the rACC or pInsL (six trials on 4 days) in response to painful electrical stimulation. The participants learned to significantly downregulate activation in pInsL and rACC and upregulate pInsL but not rACC. Success in the modulation of one region and direction of the modulation was not significantly correlated with success in another condition, indicating that the ability to control pain-related brain activation is site-specific. Less covariation between the areas in response to the nociceptive stimulus was positively correlated with learning success. Upregulation or downregulation of either region was unrelated to pain intensity or unpleasantness; however, our subjects did not learn rACC upregulation, which might be important for pain control. A significant increase in pain unpleasantness was found during upregulation of pInsL when covariation with the rACC was low. These initial results suggest that the state of the network involved in the processing of pain needs to be considered in the modulation of pain-evoked activation and its behavioral effects.

Stringaris, A., Castellanos-Ryan, N., Banaschewski, T., Barker, G. J., …, Nees, F., …, & Conrod, P. J. (2014). Dimensions of manic symptoms in youth: Psychosocial impairment and cognitive performance in the IMAGEN sample. J. Child Psychol. Psychiatry Allied Discip., 55(12), 1380–1389. PMID:24865127, doi:10.1111/jcpp.12255.

Background It has been reported that mania may be associated with superior cognitive performance. In this study, we test the hypothesis that manic symptoms in youth separate along two correlated dimensions and that a symptom constellation of high energy and cheerfulness is associated with superior cognitive performance. Method We studied 1755 participants of the IMAGEN study, of average age 14.4 years (SD = 0.43), 50.7% girls. Manic symptoms were assessed using the Development and Wellbeing Assessment by interviewing parents and young people. Cognition was assessed using the Wechsler Intelligence Scale For Children (WISC-IV) and a response inhibition task. Results Manic symptoms in youth formed two correlated dimensions: one termed exuberance, characterized by high energy and cheerfulness and one of undercontrol with distractibility, irritability and risk-taking behavior. Only the undercontrol, but not the exuberant dimension, was independently associated with measures of psychosocial impairment. In multivariate regression models, the exuberant, but not the undercontrolled, dimension was positively and significantly associated with verbal IQ by both parent- and self-report; conversely, the undercontrolled, but not the exuberant, dimension was associated with poor performance in a response inhibition task. Conclusions Our findings suggest that manic symptoms in youth may form dimensions with distinct correlates. The results are in keeping with previous findings about superior performance associated with mania. Further research is required to study etiological differences between these symptom dimensions and their implications for clinical practice.

Tzschoppe, J.*, Nees, F.*, Banaschewski, T., Barker, G. J., …, & Flor, H. (2014). Aversive learning in adolescents: Modulation by amygdala-prefrontal and amygdala-hippocampal connectivity and neuroticism. Neuropsychopharmacology, 39(4), 875–884. PMID:24126454, doi:10.1038/npp.2013.287.

Neuroticism involves a tendency for enhanced emotional and cognitive processing of negative affective stimuli and a propensity to worry and be anxious. It is known that this trait modulates fear learning and the activation of brain regions involved in it such as the amygdala, hippocampus, and prefrontal cortex and their connectivity. Thirty-nine (21 female) 14-year-old healthy adolescents participated in functional magnetic resonance imaging (fMRI) of aversive pavlovian differential delay conditioning. An unpleasant sound served as unconditioned stimulus (US) and pictures of neutral male faces as conditioned stimuli (CS+ followed by the US in 50% of the cases; CS- never followed by the US). During acquisition (CS+/- differentiation), higher levels of neuroticism were associated with a stronger interaction between the right amygdala and the right hippocampus as well as the right amygdala and prefrontal cortical regions, specifically ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex. The association of stronger conditionability of fear and connectivity of brain regions related to consolidation of fear associations and neuroticism points to underlying mechanisms of the enhanced propensity for anxiety disorders in highly neurotic participants. This is especially important in adolescence, a vulnerable time for the onset of mental disorders such as anxiety disorders.

Whelan, R., Watts, R., Orr, C. A., Althoff, R. R., …, Nees, F., …, & Garavan, H. (2014). Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature, 512(7513), 185–189. PMID:25043041, doi:10.1038/nature13402.

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention. {\textcopyright}2014 Macmillan Publishers Limited. All rights reserved.

White, T. P., Loth, E., Rubia, K., Krabbendam, L., …, Nees, F., …, & Schumann, G. (2014). Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence. Neuropsychopharmacology, 39(11), 2560–2569. PMID:24820538, doi:10.1038/npp.2014.107.

Catecholamine-0-methyl-transferase (COMT) gene variation effects on prefrontal blood oxygenation-level-dependent (BOLD) activation are robust; however, despite observations that COMT is estrogenically catabolized, sex differences in its prefrontal repercussions remain unclear. Here, in a large sample of healthy adolescents stratified by sex and Val 158 Met genotype (n=1133), we examine BOLD responses during performance of the stop-signal task in right-hemispheric prefrontal regions fundamental to inhibitory control. A significant sex-by-genotype interaction was observed in pre-SMA during successful-inhibition trials and in both pre-SMA and inferior frontal cortex during failed-inhibition trials with Val homozygotes displaying elevated activation compared with other genotypes in males but not in females. BOLD activation in the same regions significantly mediated the relationship between COMT genotype and inhibitory proficiency as indexed by stop-signal reaction time in males alone. These sexually dimorphic effects of COMT on inhibitory brain activation have important implications for our understanding of the contrasting patterns of prefrontally governed psychopathology observed in males and females.

Wicking, M., Nees, F., & Steiger, F. (2014). Neuropsychological measures of hippocampal function. Hippocampus Clin. Neurosci., 34, 60–70. PMID:24777131, doi:10.1159/000356425.

The role of the medial temporal lobe, specifically the hippocampus, in learning and memory has been consistently demonstrated over the past years and has led to the identification of the hippocampus as a target imaging marker for several neurological and psychiatric disorders. Hippocampal dysfunctions and smaller hippocampal volumes have been reported as characteristic for these disorders, and hippocampal asymmetry has been shown to be associated with memory deficits in older adults. These findings underline the importance of screenings for memory functions using neuropsychological cognitive test batteries within the clinical context. To the best of our knowledge, there has been no comprehensive review that has presented neuropsychological tests related to the hippocampus in detail. However, we did not aim to provide a complete overview of neuropsychological tests related to hippocampal function, which would fail in the light of the widespread area. This chapter focuses on neuropsychological tests that assess cognitive functions that depend on the hippocampus in a state-of-the-art fashion and additionally provide the link to several disorders for which hippocampal abnormalities are a common characteristic.

#### 2013

Cacciaglia, R., Nees, F., Pohlack, S. T., Ruttorf, M., …, & Flor, H. (2013). A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans. Biol. Psychol., 94(1), 74–81. PMID:23693003, doi:10.1016/j.biopsycho.2013.05.006.

People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-. d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning. {\textcopyright}2013 Elsevier B.V.

Gilles, M.*, Paslakis, G.*, Heinrich, A., Szostek, A., …, Nees, F., …, & Deuschle, M. (2013). A cross-over study of effects on the hypothalamus-pituitary-adrenal (HPA) axis and the sympathoadrenergic system in magnetic field strength exposure from 0 to 7 T. Stress, 16(2), 172–180. PMID:22775799, doi:10.3109/10253890.2012.708949.

The concept of stress is relevant to magnetic resonance imaging (MRI) examination in various ways. First, levels of stress to staff and patients have not been quantified in ultra-high magnetic fields. Second, research is increasingly interested in experimentally defining regional brain activity during stress. It is therefore important to know whether exposure to the ultra-high static magnetic fields per se might also lead to neurohormonal responses in the hypothalamus-pituitary-adrenal axis and the sympathoadrenal systems. In the present blinded case cross-over study with 41 healthy participants, we measured cortisol not only before and after but also during static magnetic field exposure in MRI scanners. Measures of catecholamines before and after exposure were also part of the study protocol. Using three different field strengths (1.5, 3 and 7 T) and a mock scanner (0 T), we examined whether not only the MRI procedure but also the static magnetic field per se has an influence on the neuroendocrine responses. We found no significant differences in the course of cortisol or catecholamine concentrations between the different static magnetic fields. Our study suggests that the results of MRI studies using stress-paradigms are not influenced by the static magnetic field itself. {\textcopyright}Informa Healthcare USA, Inc.

Hass, J., Walton, E., Kirsten, H., Liu, J., …, IMAGEN Consortium, & Ehrlich, S. (2013). A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype. PLoS One, 8(6). PMID:23805179, doi:10.1371/journal.pone.0064872.

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10-6 and 8.3×10-7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders. {\textcopyright}2013 Hass et al.

Heinrich, A., Lourdusamy, A., Tzschoppe, J., Vollstädt-Klein, S., …, Rietschel, M.*, & Nees, F.*. (2013). The risk variant in ODZ4 for bipolar disorder impacts on amygdala activation during reward processing. Bipolar Disord., 15(4), 440–445. PMID:23611537, doi:10.1111/bdi.12068.

Objectives: Bipolar disorder is a severe mood disorder, which normally begins during adolescence or early adulthood and has a heritability of up to 80%. The largest genome-wide association analysis of bipolar disorder recently identified a new genome-wide associated variant in OZD4 (rs12576775). The aim of the present study was to further elucidate the role of this risk variant in the disease process using an imaging genetics approach. As increased amygdala and striatal responses during the processing of reward and emotion are characteristic for bipolar disorder patients, it was tested whether the risk variant has an influence on this endophenotype in healthy adolescents. Methods: We examined the impact of the risk variant rs12576775 on functional magnetic resonance imaging data in an adolescent sample (N = 485). Differential activation between carriers of the risk allele (G-allele) and homozygous A-allele carriers in the amygdala and the striatum during a modification of the monetary incentive delay task (examining reward) and a face task (examining emotion) was analyzed. Results: Carriers of the risk allele showed an increased blood oxygen level-dependent response in the amygdala during reward sensitivity (p = 0.05) and reward expectation (p < 0.05) but not during the face task. No significant group differences were found in the striatum during both reward and emotion processing. Conclusion: Our results indicate that the ODZ4 risk variant influences reward processing in the amygdala. Alterations in the processing of emotion may have different underlying mechanisms and need to be further examined. {\textcopyright}2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Heinrich, A., Nees, F., Lourdusamy, A., Tzschoppe, J., …, & Rietschel, M. (2013). From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits. Eur. J. Neurosci., 38(6), n/a—-n/a. doi:10.1111/ejn.12201.

Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level. {\textcopyright}2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Heinrich, A., Szostek, A., Meyer, P., Nees, F., …, & Flor, H. (2013). Cognition and sensation in very high static magnetic fields: A randomized case-crossover study with different field strengths. Radiology, 266(1), 236–245. PMID:23091174, doi:10.1148/radiol.12112172.

Purpose: To establish the extent to which representative cognitive functions in subjects undergoing magnetic resonance (MR) imaging are acutely impaired by static magnetic fields of varying field strengths. Materials and Methods: This study was approved by the local ethics committee, and informed consent was obtained from all subjects. In this single-blind case-crossover study, 41 healthy subjects underwent an extensive neuropsychologic examination while in MR units of differing field strengths (1.5, 3.0, and 7.0 T), including a mock imager with no magnetic field as a control condition. Subjects were blinded to field strength. Tests were performed while subjects were lying still in the MR unit and while the examination table was moved. The tests covered a representative set of cognitive functions, such as memory, eye-hand coordination, attention, reaction time, and visual discrimination. Subjective sensory perceptions were also assessed. Effects were analyzed with a repeated-measures analysis of variance; the within-subject factors were field strength (0, 1.5, 3.0, and 7.0 T) and state (static, dynamic). Results: Static magnetic fields were not found to have a significant effect on cognitive function at any field strength. However, sensory perceptions did vary according to field strength. Dizziness, nystagmus, phosphenes, and head ringing were related to the strength of the static magnetic field. Conclusion: Static magnetic fields as high as 7.0 T did not have a significant effect on cognition. {\textcopyright}RSNA, 2012.

Lee, N. C., Krabbendam, L., White, T. P., Meeter, M., …, Nees, F., …, & Shergill, S. S. (2013). Do you see what i see? Sex differences in the discrimination of facial emotions during adolescence. Emotion, 13(6), 1030–1040. PMID:23914763, doi:10.1037/a0033560.

Montigny, C., Castellanos-Ryan, N., Whelan, R., Banaschewski, T., …, Nees, F., …, & Conrod, P. J. (2013). A phenotypic structure and neural correlates of compulsive behaviors in adolescents. PLoS One, 8(11), 1–13. PMID:24244633, doi:10.1371/journal.pone.0080151.

Nees, F.*, Witt, S. H.*, Lourdusamy, A., Vollstädt-Klein, S., …, & Flor, H. (2013). Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents. Neuropsychopharmacology, 38(11), 2081–2089. PMID:23689675, doi:10.1038/npp.2013.131.

Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes. {\textcopyright}2013 American College of Neuropsychopharmacology. All rights reserved.

Nymberg, C., Jia, T., Lubbe, S., Ruggeri, B., …, Nees, F., …, & Schumann, G. (2013). Neural mechanisms of attention-deficit/hyperactivity disorder symptoms are stratified by MAOA genotype. Biol. Psychiatry, 74(8), 607–614. PMID:23746540, doi:10.1016/j.biopsych.2013.03.027.

Schilling, C., Kühn, S., Paus, T., Romanowski, A., …, Nees, F., …, & Gallinat, J. (2013). Cortical thickness of superior frontal cortex predicts impulsiveness and perceptual reasoning in adolescence. Mol. Psychiatry, 18(5), 624–630. PMID:22665261, doi:10.1038/mp.2012.56.

Impulsiveness is a pivotal personality trait representing a core domain in all major personality inventories. Recently, impulsiveness has been identified as an important modulator of cognitive processing, particularly in tasks that require the processing of large amounts of information. Although brain imaging studies have implicated the prefrontal cortex to be a common underlying representation of impulsiveness and related cognitive functioning, to date a fine-grain and detailed morphometric analysis has not been carried out. On the basis of ahigh-resolution magnetic resonance scans acquired in 1620 healthy adolescents (IMAGEN), the individual cortical thickness (CT) was estimated. Correlations between Cloninger's impulsiveness and CT were studied in an entire cortex analysis. The cluster identified was tested for associations with performance in perceptual reasoning tasks of the Wechsler Intelligence Scale for Children (WISC IV). We observed a significant inverse correlation between trait impulsiveness and CT of the left superior frontal cortex (SFC; Monte Carlo Simulation P<0.01). CT within this cluster correlated with perceptual reasoning scores (Bonferroni corrected) of the WISC IV. On the basis of a large sample of adolescents, we identified an extended area in the SFC as a correlate of impulsiveness, which appears to be in line with the trait character of this prominent personality facet. The association of SFC thickness with perceptual reasoning argues for a common neurobiological basis of personality and specific cognitive domains comprising attention, spatial reasoning and response selection. The results may facilitate the understanding of the role of impulsiveness in several psychiatric disorders associated with prefrontal dysfunctions and cognitive deficits. {\textcopyright}2013 Macmillan Publishers Limited All rights reserved.

Schilling, C., Kühn, S., Romanowski, A., Banaschewski, T., …, IMAGEN Consortium, & Gallinat, J. (2013). Common structural correlates of trait impulsiveness and perceptual reasoning in adolescence. Hum. Brain Mapp., 34(2), 374–383. PMID:22076840, doi:10.1002/hbm.21446.

Background: Trait impulsiveness is a potential factor that predicts both substance use and certain psychiatric disorders. This study investigates whether there are common structural cerebral correlates of trait impulsiveness and cognitive functioning in a large sample of healthy adolescents from the IMAGEN project. Methods: Clusters of gray matter (GM) volume associated with trait impulsiveness, Cloningers' revised temperament, and character inventory impulsiveness (TCI-R-I) were identified in a whole brain analysis using optimized voxel-based morphometry in 115 healthy 14-year-olds. The clusters were tested for correlations with performance on the nonverbal tests (Block Design, BD; Matrix Reasoning, MT) of the Wechsler Scale of Intelligence for Children IV reflecting perceptual reasoning. Results: Cloningers' impulsiveness (TCI-R-I) score was significantly inversely associated with GM volume in left orbitofrontal cortex (OFC). Frontal clusters found were positively correlated with performance in perceptual reasoning tasks (Bonferroni corrected). No significant correlations between TCI-R-I and perceptual reasoning were observed. Conclusions: The neural correlate of trait impulsiveness in the OFC matches an area where brain function has previously been related to inhibitory control. Additionally, orbitofrontal GM volume was associated with scores for perceptual reasoning. The data show for the first time structural correlates of both cognitive functioning and impulsiveness in healthy adolescent subjects. Hum Brain Mapp, 2013. {\textcopyright}2011 Wiley Periodicals, Inc.

#### 2012

Heinrich, A., Szostek, A., Nees, F., Meyer, P., …, & Semmler, W. (2012). Response. J. Magn. Reson. Imaging, 35(1), 237. doi:10.1002/jmri.22859.
Kühn, S., Romanowski, A., Schilling, C., Banaschewski, T., …, Nees, F., …, & Gallinat, J. (2012). Manual dexterity correlating with right lobule VI volume in right-handed 14-year-olds. Neuroimage, 59(2), 1615–1621. PMID:21925277, doi:10.1016/j.neuroimage.2011.08.100.

Background: Dexterity is a fundamental skill in our everyday life. Particularly, the fine-tuning of reaching for objects is of high relevance and crucially coordinated by the cerebellum. Although neuronal cerebellar structures mediate dexterity, classical whole brain voxel-based morphometry (VBM) has not identified structural correlates of dexterity in the cerebellum. Methods: Clusters of gray matter (GM) volume associated with the Purdue Pegboard Dexterity Test, a test of fine motor skills and complex upper limb movements, were identified in a cerebellum-optimized VBM analysis using the Spatially Unbiased Infratentorial (SUIT) toolbox in 65 healthy, right-handed 14-year-olds. For comparison, classical whole brain VBM was performed. Results: The cerebellum-optimized VBM indicated a significant positive correlation between manual dexterity and GM volume in the right cerebellum Lobule VI, corrected for multiple comparisons and non-stationary smoothness. The classical whole brain VBM revealed positive associations (uncorrected) between dexterity performance and GM volume in the left SMA (BA 6), right fusiform gyrus (BA 20) and left cuneus (BA 18), but not cerebellar structures. Conclusions: The results indicate that cerebellar GM volumes in the right Lobule VI predict manual dexterity in healthy untrained humans when cerebellum-optimized VBM is employed. Although conventional VBM identified brain motor network areas it failed to detect cerebellar structures. Thus, previous studies might have underestimated the importance of cerebellum in manual dexterity. {\textcopyright}2011 Elsevier Inc.

Nees, F.*, Vollstädt-Klein, S.*, Fauth-Bühler, M., Steiner, S., …, & Flor, H. (2012). A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms? Exp. Brain Res., 223(3), 429–439. PMID:23108370, doi:10.1007/s00221-012-3272-8.

Nees, F., Diener, C., Smolka, M. N., & Flor, H. (2012). The role of context in the processing of alcohol-relevant cues. Addict. Biol., 17(2), 441–451. PMID:21790904, doi:10.1111/j.1369-1600.2011.00347.x.

In line with learning theories of drug addiction, drug-related cues may be viewed as important motivators of continued drug use. They may be differentially effective depending on the context and motivational significance. The present study aimed to test the significance of different contexts in modulating alcohol-related cue reactivity. Pictures depicting alcohol intake or its paraphernalia and pictures without any relation to alcohol intake were varied to depict physical and social contexts or different consumptive contexts associated with full/half-full/empty alcohol beverage containers. We obtained ratings of craving, valence and arousal of the cues as well as skin conductance responses (SCRs) and startle reflex modulation measures from 21 abstinent alcohol-dependent patients, recruited from an addiction treatment center, and 21 matched healthy controls. Social scenes and full glasses or bottles were rated as more pleasant and arousing compared with neutral drinking situations and empty glasses or bottles in patients. Furthermore, we found a decreased startle reflex magnitude to social compared with neutral drinking situations, and both higher SCRs and decreased startle reflex magnitude to full compared with empty glasses or bottles in patients versus controls. These results show that both physical and social and consumptive contexts differentially influence cue reactivity in abstinent alcohol-dependent patients with both social and pub-related physical contexts, and the initial consumptive context eliciting the most appetitive and arousing responses. These data have not only important implications for our understanding of the role of learning in drug dependence but also for treatment, which needs to take these factors into account. {\textcopyright}2011 Society for the Study of Addiction.

Nees, F., Tzschoppe, J., Patrick, C. J., Vollstädt-Klein, S., …, & Flor, H. (2012). Determinants of early alcohol use in healthy adolescents: The differential contribution of neuroimaging and psychological factors. Neuropsychopharmacology, 37(4), 986–995. PMID:22113088, doi:10.1038/npp.2011.282.

Pohlack, S. T.*, Nees, F.*, Ruttorf, M., Schad, L. R., & Flor, H. (2012). Activation of the ventral striatum during aversive contextual conditioning in humans. Biol. Psychol., 91(1), 74–80. PMID:22560888, doi:10.1016/j.biopsycho.2012.04.004.

The goal of this study was to investigate the function of the ventral striatum and brain regions involved in anxiety and learning during aversive contextual conditioning. Functional magnetic resonance imaging was used to assess the hemodynamic brain response of 118 healthy volunteers during a differential fear conditioning paradigm. Concurrently obtained skin conductance responses and self-reports indicated successful context conditioning. Increased hemodynamic responses in the ventral striatum during presentation of the conditioned visual stimulus that predicted the aversive event (CS+) compared to a second stimulus never paired with the aversive event (CS-) were observed in the late acquisition phase. Additionally, we found significant brain responses in the amygdala, hippocampus, insula and medial prefrontal cortex. Our data suggest the involvement of the ventral striatum during contextual fear conditioning, and underline its role in the processing of salient stimuli in general, not only during reward processing. {\textcopyright}2012 Elsevier B.V.

Pohlack, S. T., Nees, F., Liebscher, C., Cacciaglia, R., …, & Flor, H. (2012). Hippocampal but not amygdalar volume affects contextual fear conditioning in humans. Hum. Brain Mapp., 33(2), 478–488. PMID:21438079, doi:10.1002/hbm.21224.

Both animal and human studies have identified a critical role of the hippocampus in contextual fear conditioning. In humans mainly functional magnetic resonance imaging has been used. To extend these findings to volumetric properties, 58 healthy participants underwent structural magnetic resonance imaging and participated in a differential fear conditioning paradigm with contextual stimuli. Ratings of emotional valence, arousal, and contingency as well as skin conductance responses (SCRs) were used as indicators of conditioning. Twenty-nine participants with the smallest hippocampal volumes were compared with 29 persons with the largest hippocampal volumes. Persons with larger hippocampal volume (especially on the right side) learned to discriminate between two conditioned contexts, whereas those with small hippocampal volumes did not, as indicated by SCRs. Further analyses showed that these results could not be explained by amygdalar volumes. In contrast, the participant answers on the self-report measures were not significantly influenced by hippocampal or amygdalar, but by total brain volume, suggesting a role of cortical structures in these more cognitive evaluation processes. Reanalysis of the self-report data using partial hippocampal volumes revealed a significant influence of the posterior but not anterior subvolumes, which is in accordance with theories and empirical findings on hippocampal functioning. This study shows the relevance of hippocampal volume for contextual fear conditioning in healthy volunteers and may have important implications for anxiety disorders. {\textcopyright}2011 Wiley Periodicals, Inc.

Ridder, S., Treutlein, J., Nees, F., Lang, S., …, & Flor, H. (2012). Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic-pituitary-adrenal axis: first evidence from two independent subsamples. Psychol. Med., 42(11), 2325–2335. PMID:22410078, doi:10.1017/S0033291712000359.

BACKGROUND: Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis. METHOD: In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. RESULTS: Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala-prefrontal connectivity. CONCLUSIONS: This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.

Schneider, S., Brassen, S., Bromberg, U., Banaschewski, T., …, Nees, F., …, & Büchel, C. (2012). Maternal interpersonal affiliation is associated with adolescents' brain structure and reward processing. Transl. Psychiatry, 2(September). PMID:23149446, doi:10.1038/tp.2012.113.

Considerable animal and human research has been dedicated to the effects of parenting on structural brain development, focusing on hippocampal and prefrontal areas. Conversely, although functional imaging studies suggest that the neural reward circuitry is involved in parental affection, little is known about mothers' interpersonal qualities in relation to their children's brain structure and function. Moreover, gender differences concerning the effect of maternal qualities have rarely been investigated systematically. In 63 adolescents, we assessed structural and functional magnetic resonance imaging as well as interpersonal affiliation in their mothers. This allowed us to associate maternal affiliation with gray matter density and neural responses during different phases of the well-established Monetary Incentive Delay task. Maternal affiliation was positively associated with hippocampal and orbitofrontal gray matter density. Moreover, in the feedback of reward hit as compared with reward miss, an association with caudate activation was found. Although no significant gender effects were observed in these associations, during reward feedback as compared with baseline, maternal affiliation was significantly associated with ventral striatal and caudate activation only in females. Our findings demonstrate that maternal interpersonal affiliation is related to alterations in both the brain structure and reward-related activation in healthy adolescents. Importantly, the pattern is in line with typical findings in depression and post-traumatic stress disorder, suggesting that a lack of maternal affiliation might have a role in the genesis of mental disorders. {\textcopyright}2012 Macmillan Publishers Limited All rights reserved.

Schneider, S., Peters, J., Bromberg, U., Brassen, S., …, Nees, F., …, & Büchel, C. (2012). Risk taking and the adolescent reward system: A potential common link to substance abuse. Am. J. Psychiatry, 169(1), 39–46. PMID:21955931, doi:10.1176/appi.ajp.2011.11030489.

Objective: Increased risk-taking behavior has been associated with addiction, a disorder also linked to abnormalities in reward processing. Specifically, an attenuated response of reward-related areas (e.g., the ventral striatum) to non-drug reward cues has been reported in addiction. One unanswered question is whether risk-taking preference is associated with striatal reward processing in the absence of substance abuse. Method: Functional and structural MRI was performed in 266 healthy young adolescents and in 31 adolescents reporting potentially problematic substance use. Activation during reward anticipation (using the monetary incentive delay task) and to gray matter density were measured. Risk-taking bias was assessed by the Cambridge Gamble Task. Results: With increasing risk-taking bias, the ventral striatum showed decreased activation bilaterally during reward anticipation. Voxel-based morphometry showed that greater risk-taking bias was also associated with and partially mediated by lower gray matter density in the same structure. The decreased activation was also observed when participants with virtually any substance use were excluded. The group with potentially problematic substance use showed greater risk taking as well as lower striatal activation relative to matched comparison subjects from the main sample. Conclusions: Risk taking and functional and structural properties of the reward system in adolescents are strongly linked prior to a possible onset of substance abuse, emphasizing their potential role in the predisposition to drug abuse.

Stacey, D., Bilbao, A., Maroteaux, M., Jia, T., …, Nees, F., …, & Schumann, G. (2012). RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. Proc. Natl. Acad. Sci., 109(51), 21128–21133. PMID:23223532, doi:10.1073/pnas.1211844110.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association meta-analysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca 2+-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in bothmice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2-/- mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2-/- mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the IA potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous meta-analysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

Stein, J. L., Medland, S. E., Vasquez, A. A., Hibar, D. P., …, IMAGEN Consortium, & Fernández, G. (2012). Identification of common variants associated with human hippocampal and intracranial volumes. Nat. Genet., 44(5), 552–561. PMID:22504417, doi:10.1038/ng.2250.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10 -16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10 -12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10 -7). {\textcopyright}2012 Nature America, Inc. All rights reserved.

Tahmasebi, A. M., Artiges, E., Banaschewski, T., Barker, G. J., …, & IMAGEN Consortium. (2012). Creating probabilistic maps of the face network in the adolescent brain: A multicentre functional MRI study. Hum. Brain Mapp., 33(4), 938–957. PMID:21416563, doi:10.1002/hbm.21261.

Large-scale magnetic resonance (MR) studies of the human brain offer unique opportunities for identifying genetic and environmental factors shaping the human brain. Here, we describe a dataset collected in the context of a multi-centre study of the adolescent brain, namely the IMAGEN Study. We focus on one of the functional paradigms included in the project to probe the brain network underlying processing of ambiguous and angry faces. Using functional MR (fMRI) data collected in 1,110 adolescents, we constructed probabilistic maps of the neural network engaged consistently while viewing the ambiguous or angry faces; 21 brain regions responding to faces with high probability were identified. We were also able to address several methodological issues, including the minimal sample size yielding a stable location of a test region, namely the fusiform face area (FFA), as well as the effect of acquisition site (eight sites) and scanner (four manufacturers) on the location and magnitude of the fMRI response to faces in the FFA. Finally, we provided a comparison between male and female adolescents in terms of the effect sizes of sex differences in brain response to the ambiguous and angry faces in the 21 regions of interest. Overall, we found a stronger neural response to the ambiguous faces in several cortical regions, including the fusiform face area, in female (vs. male) adolescents, and a slightly stronger response to the angry faces in the amygdala of male (vs. female) adolescents. {\textcopyright}2011 Wiley Periodicals, Inc.

Thyreau, B., Schwartz, Y., Thirion, B., Frouin, V., …, IMAGEN Consortium, & Poline, J.-B. (2012). Very large fMRI study using the IMAGEN database: Sensitivity–specificity and population effect modeling in relation to the underlying anatomy. Neuroimage, 61(1), 295–303. PMID:22425669, doi:10.1016/j.neuroimage.2012.02.083.

In this paper we investigate the use of classical fMRI Random Effect (RFX) group statistics when analyzing a very large cohort and the possible improvement brought from anatomical information. Using 1326 subjects from the IMAGEN study, we first give a global picture of the evolution of the group effect t-value from a simple face-watching contrast with increasing cohort size. We obtain a wide activated pattern, far from being limited to the reasonably expected brain areas, illustrating the difference between statistical significance and practical significance. This motivates us to inject tissue-probability information into the group estimation, we model the BOLD contrast using a matter-weighted mixture of Gaussians and compare it to the common, single-Gaussian model. In both cases, the model parameters are estimated per-voxel for one subgroup, and the likelihood of both models is computed on a second, separate subgroup to reflect model generalization capacity. Various group sizes are tested, and significance is asserted using a 10-fold cross-validation scheme. We conclude that adding matter information consistently improves the quantitative analysis of BOLD responses in some areas of the brain, particularly those where accurate inter-subject registration remains challenging. {\textcopyright}2012 Elsevier Inc.

Whelan, R., Conrod, P. J., Poline, J.-B., Lourdusamy, A., …, Nees, F., …, & Garavan, H. (2012). Adolescent impulsivity phenotypes characterized by distinct brain networks. Nat. Neurosci., 15(6), 920–925. PMID:22544311, doi:10.1038/nn.3092.

The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior. {\textcopyright}2012 Nature America, Inc. All rights reserved.

#### 2011

Heinrich, A., Szostek, A., Nees, F., Meyer, P., …, & Flor, H. (2011). Effects of static magnetic fields on cognition, vital signs, and sensory perception: A meta-analysis. J. Magn. Reson. Imaging, 34(4), 758–763. PMID:21751291, doi:10.1002/jmri.22720.

To evaluate whether cognitive processes, sensory perception, and vital signs might be influenced by static magnetic fields in magnetic resonance imaging (MRI), which could pose a risk for health personnel and patients, we conducted a meta-analysis of studies that examined effects of static magnetic fields. Studies covering the time from 1992 to 2007 were selected. Cohen's d effects sizes were used and combined in different categories of neuropsychology (reaction time, visual processing, eye-hand coordination, and working memory). Additionally, effects of static magnetic fields on sensory perception and vital signs were analyzed. In the category "neuropsychology," only effects on the visual system were homogeneous, showing a statistically significant impairment as a result of exposure to static magnetic fields (d = -0.415). Vital signs were not affected and effects on sensory perceptions included an increase of dizziness and vertigo, primarily caused by movement during static magnetic field gradient exposures. The number of studies dealing with this topic is very small and the experimental set-up of some of the analyzed studies makes it difficult to accurately determine the effects of static magnetic fields by themselves, excluding nonspecific factors. The implications of these results for MRI lead to suggestions for improvement in research designs. Copyright {\textcopyright}2011 Wiley-Liss, Inc.

Peters, J., Bromberg, U., Schneider, S., Brassen, S., …, IMAGEN Consortium, & Büchel, C. (2011). Lower ventral striatal activation during reward anticipation in adolescent smokers. Am. J. Psychiatry, 168(5), 540–549. PMID:21362742, doi:10.1176/appi.ajp.2010.10071024.

Objective: Adolescents are particularly vulnerable to addiction, and in the case of smoking, this often leads to long-lasting nicotine dependence. The authors investigated a possible neural mechanism underlying this vulnerability. Method: Functional MRI was performed during reward anticipation in 43 adolescent smokers and 43 subjects matched on age, gender, and IQ. The authors also assessed group differences in novelty seeking, impulsivity, and reward delay discounting. Results: In relation to the comparison subjects, the adolescent smokers showed greater reward delay discounting and higher scores for novelty seeking. Neural responses in the ventral striatum during reward anticipation were significantly lower in the smokers than in the comparison subjects, and in the smokers this response was correlated with smoking frequency. Notably, the lower response to reward anticipation in the ventral striatum was also observed in smokers (N=14) who had smoked on fewer than 10 occasions. Conclusions: The present findings suggest that a lower response to reward anticipation in the ventral striatum may be a vulnerability factor for the development of early nicotine use.

Pohlack, S. T., Nees, F., Ruttorf, M., Witt, S. H., …, & Flor, H. (2011). Risk variant for schizophrenia in the neurogranin gene impacts on hippocampus activation during contextual fear conditioning. Mol. Psychiatry, 16(11), 1072–1073. PMID:21647148, doi:10.1038/mp.2011.66.
Ruscheweyh, R.*, Nees, F.*, Marziniak, M., Evers, S., …, & Knecht, S. (2011). Pain Catastrophizing and Pain-related Emotions. Clin. J. Pain, 27(7), 578–586. doi:10.1097/AJP.0b013e31820fde1b.

Objectives: One of the most important determinants of the individual pain experience is pain catastrophizing, reflecting an excessively negative cognitive and emotional orientation toward pain. Its assessment by standard questionnaires, which ask participants to reflect on idiosyncratic past painful experiences, is important. It is currently not known whether different types of pain differently shape pain catastrophizing. Furthermore, as the regulation of emotions changes during the life span, age may affect pain catastrophizing, as well. Methods: In this study, 134 healthy participants, differentiated into 2 age groups (20 to 40 y and 50 to 70 y), completed the Pain Catastrophizing Scale with reference to their past experiences with 3 common types of day-to-day pain (headache, back pain, dental pain). Results: On average, the different types of pain shared one-third of the variance in pain catastrophizing. Pain-type-specific catastrophizing scores were more strongly related to ratings of sensory and emotional pain characteristics than standard catastrophizing scores. In younger adults, pain catastrophizing was preferentially associated with emotional responses to pain whereas in older adults, it was preferentially associated with pain intensity ratings. Discussion: This study indicates that for day-to-day pain, catastrophizing significantly depends on pain type. The results suggest the use of pain-type-specific instructions for catastrophizing questionnaires because it may lead to better prediction of clinically relevant pain characteristics, such as pain intensity. Furthermore, pain catastrophizing seems to change during the life span, with a higher engagement of emotional versus sensory pain processing in younger compared with older adults. Copyright {\textcopyright}2011 by Lippincott Williams & Wilkins.

Schneider, S., Peters, J., Bromberg, U., Brassen, S., …, IMAGEN Consortium, & Büchel, C. (2011). Boys do it the right way: Sex-dependent amygdala lateralization during face processing in adolescents. Neuroimage, 56(3), 1847–1853. PMID:21316467, doi:10.1016/j.neuroimage.2011.02.019.

Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder). {\textcopyright}2011 Elsevier Inc.

#### 2010

Nees, F., Rüddel, H., Mussgay, L., Kuehl, L. K., …, & Schächinger, H. (2010). Alteration of Delay and Trace Eyeblink Conditioning in Fibromyalgia Patients. Psychosom. Med., 72(4), 412–418. PMID:20190129, doi:10.1097/PSY.0b013e3181d2bbef.

OBJECTIVE: Classical conditioning processes are important for the generation and persistence of symptoms in psychosomatic disorders, such as the fibromyalgia syndrome (FMS). Pharmacologically induced hyper-and hypocortisolism were shown to affect trace but not delay classical eyeblink conditioning. As previous studies revealed a relative hypocortisolism in FMS patients, we hypothesized that FMS patients also show altered eyeblink conditioning. METHODS: FMS patients (n = 30) and healthy control subjects (n = 20) matched for gender and age were randomly assigned to a delay or trace eyeblink conditioning protocol, where conditioned eyeblink response probability was assessed by electromyogram. Morning cortisol levels, ratings of depression, anxiety as well as psychosomatic complaints, general symptomatology, and psychological distress were assessed. RESULTS: As compared with healthy controls, FMS patients showed lower morning cortisol levels, corroborating previously described disturbances in neuroendocrine regulation of the hypothalamus-pituitary-adrenal axis in these patients. Trace eyeblink conditioning was facilitated in FMS patients, whereas delay eyeblink conditioning was reduced, and cortisol measures correlated significantly only with trace eyeblink conditioning. CONCLUSION: We conclude that FMS patients characterized by decreased cortisol levels differ in classical trace eyeblink conditioning from healthy controls, suggesting that endocrine mechanisms affecting hippocampus-mediated forms of associative learning may play a role in the generation of symptoms in these patients. {\textcopyright}2010 by the American Psychosomatic Society.

Schumann, G., Loth, E., Banaschewski, T., Barbot, A., …, IMAGEN Consortium, & Struve, M. (2010). The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology. Mol. Psychiatry, 15(12), 1128–1139. PMID:21102431, doi:10.1038/mp.2010.4.

A fundamental function of the brain is to evaluate the emotional and motivational significance of stimuli and to adapt behaviour accordingly. The IMAGEN study is the first multicentre genetic-neuroimaging study aimed at identifying the genetic and neurobiological basis of individual variability in impulsivity, reinforcer sensitivity and emotional reactivity, and determining their predictive value for the development of frequent psychiatric disorders. Comprehensive behavioural and neuropsychological characterization, functional and structural neuroimaging and genome-wide association analyses of 2000 14-year-old adolescents are combined with functional genetics in animal and human models. Results will be validated in 1000 adolescents from the Canadian Saguenay Youth Study. The sample will be followed up longitudinally at the age of 16 years to investigate the predictive value of genetics and intermediate phenotypes for the development of frequent psychiatric disorders. This review describes the strategies the IMAGEN consortium used to meet the challenges posed by large-scale multicentre imaging-genomics investigations. We provide detailed methods and Standard Operating Procedures that we hope will be helpful for the design of future studies. These include standardization of the clinical, psychometric and neuroimaging-acquisition protocols, development of a central database for efficient analyses of large multimodal data sets and new analytic approaches to large-scale genetic neuroimaging analyses. {\textcopyright}2010 Macmillan Publishers Limited All rights reserved.

#### 2009

Lass-Hennemann, J., Schulz, A., Nees, F., Blumenthal, T. D., & Schachinger, H. (2009). Direct gaze of photographs of female nudes influences startle in men. Int. J. Psychophysiol., 72(2), 111–114. PMID:19028531, doi:10.1016/j.ijpsycho.2008.11.001.

Foreground presentation of photographs of opposite sex nudes lowers startle elicited by sudden acoustic stimuli. However, the impact of gaze direction of the presented nudes on this startle modulation has not been investigated. Theoretically, direct gaze of photographs of female nudes could either lead to a larger inhibition of the startle reaction due to a summating valence and arousal effect of direct eye contact, or lead to a smaller inhibition due to an attention capturing effect of the eyes. Two subsets of erotic photographs of female nudes (women looking directly at the observer vs. gazing away) and standard IAPS neutral pictures were viewed by 26 male volunteers, while startle eye blink responses to binaural bursts of white noise (50 ms, 105 dB) were recorded by EMG. Erotic pictures reduced startle eyeblink magnitude as compared to neutral pictures. Furthermore, erotic stimuli without direct gaze at the observer showed a greater startle eyeblink inhibition than erotic stimuli with direct gaze at the observer. Our data suggest that direct gaze of opposite sex nudes may direct attention to the face, thereby reducing the appetitive impact of an attractive body. {\textcopyright}2008 Elsevier B.V. All rights reserved.

Nees, F., Hahn, M., Schulz, A., Blumenthal, T. D., & Schächinger, H. (2009). Aversive associative conditioning of prepulses in a startle inhibition paradigm. Psychophysiology, 46(3), 481–486. PMID:19226308, doi:10.1111/j.1469-8986.2009.00792.x.

Prepulse inhibition of startle (PPI) represents an automatic mechanism that reflects sensorimotor gating and early attention processes. PPI neither is the consequence of conscious behavioral modulation nor does it depend on learning and conditioning. However, pairing of weak tones and aversive startle stimuli during PPI testing may induce associative learning. Thus, in the present study (n=60) we tested whether prepulses may be subject to aversive conditioning. Eyeblink EMG and electrodermal responses to intense (100 dB) acoustic stimuli, presented either alone or preceded by weak tones (prepulses, 50 ms, 70 dB, SOA=120 ms), were measured. We found that after strong contingent pairing of weak tones with startle stimuli (PPI paradigm) intense versions of these tones induced significantly larger eyeblink and skin conductance responses than did never paired control tones. We conclude that during PPI testing, prepulses may be subject to aversive conditioning. Copyright {\textcopyright}2009 Society for Psychophysiological Research.

Roemer, S., Nees, F., Richter, S., Blumenthal, T. D., & Schächinger, H. (2009). Endogenous cortisol suppression with metyrapone enhances acoustic startle in healthy subjects. Horm. Behav., 55(2), 314–318. PMID:19071128, doi:10.1016/j.yhbeh.2008.11.003.

Previous human studies have shown that excess cortisol sufficient to fully occupy central nervous system (CNS) corticosteroid receptors may reduce startle eye blink. The present study tested whether cortisol depletion and the resulting reduction in activity of CNS corticosteroid receptors has the opposite effect. In a single-blind, placebo-controlled, randomized study, eye blink EMG responses to 105 dB acoustic startle stimuli were assessed in 25 healthy subjects who received oral metyrapone (1500 mg) to suppress endogenous cortisol production, while 24 controls received oral placebo. As expected, metyrapone significantly reduced salivary cortisol, indicating effective endogenous cortisol suppression. Startle eye blink responses were significantly increased in the metyrapone group. Short-term habituation of the startle reflex was not different between groups. Our results suggest that startle is enhanced during depletion of cortisol. This effect may be mediated by CNS mechanisms controlling cortisol feedback. {\textcopyright}2008 Elsevier Inc.

Schulz, A., Lass-Hennemann, J., Nees, F., Blumenthal, T. D., …, & Schachinger, H. (2009). Cardiac modulation of startle eye blink. Psychophysiology, 46(2), 234–240. PMID:19207206, doi:10.1111/j.1469-8986.2008.00768.x.

As an alternative to interoceptive paradigms that depend on the participants' active cooperation, two studies are presented to show that startle methodology may be employed to study visceral afferent processing. The first study of 38 volunteers showed that startle responses were smaller when elicited during cardiac systole as compared to diastole. In the second study, 31 diabetic patients were divided into two groups, having normal or diminished (<6 ms/mmHg) baroreflex sensitivity (BRS). Patients with normal BRS showed the same results found in healthy volunteers. Diabetic patients with diminished BRS did not show this pattern. Because diminished BRS is an indicator of impaired baro-afferent signal transmission, it is concluded that cardiac modulation of startle is associated with intact baro-afferent feedback. Thus, pre-attentive startle methodology is feasible to study visceral afferent processing originating from the cardiovascular system. Copyright {\textcopyright}2009 Society for Psychophysiological Research.

#### 2008

Nees, F., Richter, S., Lass-Hennemann, J., Blumenthal, T. D., & Schächinger, H. (2008). Inhibition of cortisol production by metyrapone enhances trace, but not delay, eyeblink conditioning. Psychopharmacology (Berl)., 199(2), 183–190. PMID:18478206, doi:10.1007/s00213-008-1155-2.

Rationale: Hypocortisolism impairs trace classical conditioning of the eyeblink response to an air puff but does not affect delay conditioning. Objectives: The opposite neurohormonal condition, hypocortisolism, may facilitate trace classical conditioning, which might be informative in understanding the role of classical conditioning in stress-sensitive syndromes such as fibromyalgia. Materials and methods: Volunteers (n=82) were randomized to receive either an inhibitor of cortisol production (metyrapone, 1500 mg) or placebo and to complete a delay or a trace eyeblink conditioning protocol (unconditioned stimulus: corneal air puff, 10 psi, 50 ms; conditioned stimulus: binaural pure tone, 75 dB, 1000 Hz, 400 ms; empty interval in trace conditioning: 600 ms), where conditioned eyeblink response probability was assessed electromyographically. Results: Metyrapone induced hypocortisolism, reflected by a 30% decrease of salivary cortisol levels (p<0.01), and facilitated trace eyeblink conditioning (p<0.001), while delay eyeblink conditioning remained unaffected. Moreover, extinction of delay-conditioned eyeblink responses was impaired (p=0.023), but extinction of trace-conditioned responses remained unaffected. Conclusions: We conclude that acute mild metyrapone-induced hypocortisolism facilitates hippocampus-mediated classical trace eyeblink conditioning but suppresses the extinction of cerebellum-based delay-conditioned responses. Both results may be of theoretical and clinical significance for the generation and persistence of psychosomatic symptoms in patient groups characterized by relative hypocortisolism (e.g., fibromyalgia and chronic fatigue). {\textcopyright}2008 Springer-Verlag.

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