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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.

Appelhoff, S., & Stenner, T. (2021). In COM we trust: Feasibility of USB-based event marking. Behavior Research Methods. PMID:33852129, doi:10.3758/s13428-021-01571-z.

Modern experimental research often relies on the synchronization of different events prior to data analysis. One way of achieving synchronization involves marking distinct events with electrical pulses (event markers or “TTL pulses”), which are continuously recorded with research hardware, and can later be temporally aligned. Traditionally, this event marking was often performed using the parallel port in standard personal computers. However, the parallel port is disappearing from the landscape of computer hardware, being replaced by a serial (COM) port, namely the USB port. To find an adequate replacement for the parallel port, we evaluated four microcontroller units (MCUs) and the LabJack U3, an often-used USB data acquisition device, in terms of their latency and jitter for sending event markers in a simulated experiment on both Windows and Linux. Our results show that all four MCUs were comparable to the parallel port in terms of both latency and jitter, and consistently achieved latencies under 1 ms. With some caveats, the LabJack U3 can also achieve comparable latencies. In addition to the collected data, we share extensive documentation on how to build and use MCUs for event marking, including code examples. MCUs are a cost-effective, flexible, and performant replacement for the disappearing parallel port, enabling event marking and synchronization of data streams.

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.

Background Frailty is characterized by an age-related decline in multiple physiological systems, leading to a high vulnerability to stressors, adverse health outcomes, and low quality of life. Neuroscientific models of pathological aging emphasize the loss of sensorimotor stimulation and reduced neuromodulatory capacities as core processes in age-related cognitive and bodily decline, which may be associated with maladaptive plastic changes in the brain. We plan to increase sensorimotor stimulation in frail persons through a newly developed app-based training program and link the training trials to biological and psychological correlates of age-associated vulnerability and health indices. Methods We will conduct a randomized trial, applying an app-based sensorimotor home training (N = 30) in people suffering from frailty. An app-based relaxation training will serve as an active control condition (N = 30). Both interventions will last for 90 days each. The sensorimotor training includes unimodal and multimodal sensory discrimination tasks in the visual, auditory, and tactile domain, as well as sensorimotor precision tasks. The tasks will be implemented using an adaptive training algorithm and enriched with motivational components embedded in a virtual training environment. We expect a pre-post reduction of frailty status and associated functional decline related to refinement of representational maps within the sensorimotor system and improved sensorimotor function such as extremity function. Secondary analyses will study the influence of BDNF genotype as moderating variable. Additional outcomes will include measures of perceptual and cognitive functioning, quality of life as well as BDNF serum levels. Measurements will take place before training (baseline), after 60 days (assessment 1), and at the end of the training after 90 days (assessment 2). Discussion In our randomized trial, we aim to characterize a multidimensional concept of frailty and to target maladaptive behaviors and neuroplasticity using an app-based sensorimotor training. This type of intervention might provide further knowledge and new possibilities for preventing decline and preserving function in older adults.

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.

Brauer, H., Breitling-Ziegler, C., Moliadze, V., Galling, B., & Prehn-Kristensen, A. (2021). Transcranial direct current stimulation in attention-deficit/hyperactivity disorder: A meta-analysis of clinical efficacy outcomes. In Kadosh, R. C., Zaehle, T., & Krauel, K. (Eds.), Non-invasive Brain Stimulation (NIBS) in Neurodevelopmental Disorders (pp. 91–116). Elsevier.
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.

Grill, S., Yahiaoui-Doktor, M., Basrai, M., Struck, J., …, Niederberger, U., …, & Kiechle, M. (2021). Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers. Breast cancer research and treatment, 186(3), 741–752. PMID:33543354, doi:10.1007/s10549-020-06070-x.

BACKGROUND Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)-involved in tumorigenesis and obesity-related diseases-are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC. METHODS The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors. RESULTS At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = - 0.435; CI - 0.653 to - 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061-0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: - 37.9, p = 0.097/0.080) in multivariate analysis. CONCLUSION Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Hunold, A., Haueisen, J., Freitag, C. M., Siniatchkin, M., & Moliadze, V. (2021). Cortical current density magnitudes during transcranial direct current stimulation correlate with skull thickness in children, adolescent and young adults. In Kadosh, R. C., Zaehle, T., & Krauel, K. (Eds.), Non-invasive Brain Stimulation (NIBS) in Neurodevelopmental Disorders (pp. 41–56). Elsevier.
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.

Kropp, P., Niederberger, U., & Dresler, T. (2021). Wirkungsweise und Anwendung des Biofeedbacks am Beispiel von Kopfschmerzen. Psychotherapeut. doi:10.1007/s00278-021-00499-1.
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.

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.

Salvador, R., Biagi, M. C., Puonti, O., Splittgerber, M., Moliadze, V., …, & Ruffini, G. (2021). Personalization of Multi-electrode Setups in tCS/tES: Methods and Advantages. In Makarov, S., & , Noetscher, Gregory, Nummenmaa, A. (Eds.), Brain Hum. Body Model. 2020 (1st ed., pp. 119–135). Cham: Springer International Publishing.
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.


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.

BACKGROUND Mindfulness training (MT) for parents of adolescents has been shown to improve mental health and stress-related outcomes in individuals and their families. Studies of MT among young people are mainly delivered in educational or clinical settings, and there is a need for controlled studies on both parent-directed and adolescent-directed approaches. It is unclear whether MT has preventive effects for substance use outcomes. The primary objective of this trial is to evaluate the effectiveness of family-based MT targeting both adolescents and their parents to prevent adolescent substance use and enhance neurobehavioral self-regulation skills that play a major role in addiction development and mental health. METHODS/DESIGN The trial design is a superiority, two-arm, randomized controlled trial in which families will participate either in the full curriculum of the evidence-based Strengthening Families Program 10-14 (SFP 10-14, German adaptation) or in a mindfulness-enhanced version of this program (SFP-Mind). Both seven-session interventions are highly structured and will each be delivered over a period of approximately 7 weeks. The experimental intervention SFP-Mind is a modified version of the SFP 10-14 in which some elements were eliminated or changed to enable the inclusion of additional parent-directed and adolescent-directed mindfulness components. The primary outcome is adolescent self-reported alcohol use based on an alcohol initiation index at 18-month follow-up. Dispositional mindfulness, impulsivity, and emotion regulation will be included as secondary outcomes and potential mechanisms of action. The study will recruit and randomize 216 adolescents, aged 10-14 years, and their parents who will be followed up for 18 months. DISCUSSION This trial aims to evaluate the effectiveness of SFP-Mind for family-based prevention of substance use and promoting mental health in adolescence. TRIAL REGISTRATION German Register of Clinical Studies, DRKS00015678. Registered on 25 February 2019.

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.

Galka, A., Moontaha, S., & Siniatchkin, M. (2020). Constrained expectation maximisation algorithm for estimating ARMA models in state space representation. EURASIP J. Adv. Signal Process., 2020(1), 23. doi:10.1186/s13634-020-00678-3.

This paper discusses the fitting of linear state space models to given multivariate time series in the presence of constraints imposed on the four main parameter matrices of these models. Constraints arise partly from the assumption that the models have a block-diagonal structure, with each block corresponding to an ARMA process, that allows the reconstruction of independent source components from linear mixtures, and partly from the need to keep models identifiable. The first stage of parameter fitting is performed by the expectation maximisation (EM) algorithm. Due to the identifiability constraint, a subset of the diagonal elements of the dynamical noise covariance matrix needs to be constrained to fixed values (usually unity). For this kind of constraints, so far, no closed-form update rules were available. We present new update rules for this situation, both for updating the dynamical noise covariance matrix directly and for updating a matrix square-root of this matrix. The practical applicability of the proposed algorithm is demonstrated by a low-dimensional simulation example. The behaviour of the EM algorithm, as observed in this example, illustrates the well-known fact that in practical applications, the EM algorithm should be combined with a different algorithm for numerical optimisation, such as a quasi-Newton algorithm.

Gerber, W.-D., Niederberger, U., & Siniatchkin, M. (2020). Schmerzen. In Petermann, F. (Ed.), Entspannungsverfahren (pp. 253–267). Weinheim: Beltz.
Göbel, C. H., Göbel, A., Niederberger, U., Heinze, A., …, & Göbel, H. (2020). Occipital Nerve Stimulation in Chronic Migraine: The Relationship Between Perceived Sensory Quality, Perceived Sensory Location, and Clinical Efficacy—A Prospective, Observational, Non-Interventional Study. Pain Ther., 9(2), 615–626. PMID:32910427, doi:10.1007/s40122-020-00194-0.

INTRODUCTION: Occipital nerve stimulation (ONS) is used to treat therapy-resistant chronic migraine. Clinical use has resulted in a wide intraindividual and interindividual variation of clinical efficacy. The aim of this study was to analyze a potential relationship between sociodemographic variables, headache parameters, perceived sensory quality, perceived sensory location, as well as clinical efficacy. METHODS: Thirty-two subjects (21.9% male, mean age 45.77 years) suffering from chronic migraine refractory to other treatment and therefore treated with ONS were included in this study. We used a computer-based imaging method for mapping the ONS-induced perceived sensory location, the perceived spatial sensory field size, as well as the perceived sensory quality in a long-term course over 21 months in weekly time intervals. Additionally, the effect of ONS on the migraine headache was documented weekly by the participants using a verbal rating scale. Over the observation period, a total of 808 individual weekly data sets were recorded and a potential relationship between ONS-induced perceptions and headache parameters could be analyzed. RESULTS: We found that 48.9% of stimulation intervals were reported as effective by patients. Women displayed a significantly higher responder rate than men. The reported effectiveness did not differ depending on age, the average number of migraine days per month, the MIDAS score, or the duration of the migraine disorder prior to ONS treatment. Implantation with trial period led to significantly lower responder rates than without the trial period. The most frequently perceived sensory quality of "tingling" was found significantly more frequently in non-responders than in responders. Responders displayed significantly lower pleasantness scores for their reported perceptions than non-responders. Sensations that were spatially perceived above the line connecting the external acoustic meati with the external occipital protuberance (MOP line) led to patients reporting a positive clinical effect significantly more frequently than sensations spatially perceived below the MOP line. Spatially small fields of sensory perception were correlated with a higher responder rate than those covering broader areas. CONCLUSIONS: The ONS-induced sensory location, the size of the spatial sensory field, as well as the sensory quality are significantly correlated with the reported clinical effectiveness. The results suggest that besides surgical technique, the individual and continuous programming of the stimulation parameters is clinically relevant in increasing the therapeutic effectiveness.

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.

Hamid, L., Habboush, N., Stern, P., Japaridze, N., …, Galka, A., & Siniatchkin, M. (2020). Source imaging of deep-brain activity using the regional spatiotemporal Kalman filter. Comput. Methods Programs Biomed., p. 105830. doi:10.1016/j.cmpb.2020.105830.
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.

Kadish, N. E., Riedel, C., Stephani, U., & Wiegand, G. (2020). Developmental outcomes in children/adolescents and one adult with tuberous sclerosis complex (TSC) and refractory epilepsy treated with everolimus. Epilepsy Behav., 111, 107182. PMID:32535369, doi:10.1016/j.yebeh.2020.107182.

This prospective observational study focuses on developmental outcomes in the treatment of tuberous sclerosis complex (TSC) with everolimus (EVO). Fourteen children/adolescents aged 1.7–13.07 and one adult aged 31 years, all with TSC and refractory epilepsy participated. All were treated with EVO for 3–70 months (md: 37). Development/adaptive functioning were evaluated at baseline with follow-up in 11 patients; all patients were assessed during the course of treatment. Our exploratory analyses included factors contributing to developmental impairment and change from baseline to last evaluation. The majority of patients showed severe developmental impairment (86%). Patients with a higher age at inclusion, duration of epilepsy, and number of previous antiepileptic drugs (AEDs) showed lower developmental levels. Earlier onset of epilepsy and a higher number of current AEDs were associated with worse adaptive functioning. At their last examination, four patients were seizure-free (27%), and four experienced a reduction of seizures > 50% (27%). With treatment, (slight) increase was seen in absolute values of developmental age (DA) regarding both development and adaptive functioning. Yet, when accounting for age, decrease was seen in both assessments. While developmental disorders were prominent, we observed an overall progression at a slower pace. Despite a positive effect on seizure occurrence, treatment with EVO did not reverse developmental problems in the observation period of this study.

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.

Merkt, J., Siniatchkin, M., & Petermann, F. (2020). Neuropsychological Measures in the Diagnosis of ADHD in Preschool: Can Developmental Research Inform Diagnostic Practice? J. Atten. Disord., 24(11), 1588–1604. PMID:27006414, doi:10.1177/1087054716629741.

Objective: The diagnosis of ADHD in preschool is challenging. Behavioral ratings are less reliable, but the value of neuropsychological tests in the diagnosis of ADHD has been debated. Method: This article provides an overview of neuropsychological measures utilized in preschoolers with ADHD (3-5 years). In addition, the manuscript discusses the extent to which these measures have been tested for their diagnostic capacity. Results: The diagnostic utility of computerized continuous performance tests and working memory subtests from IQ-batteries has been demonstrated in a number of studies by assessing their psychometric properties, sensitivity, and specificity. However, findings from developmental and basic research attempting to describe risk factors that explain variance in ADHD show the most consistent associations of ADHD with measures of delay aversion. Conclusion: Results from developmental research could benefit studies that improve ADHD diagnosis at the individual level. It might be helpful to consider testing as a structured situation for behavioral observation by the clinician.

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.

Moliadze, V.*, Brodski-Guerniero, A.*, Schuetz, M., Siemann, J., Lyzhko, E., …, & Siniatchkin, M. (2020). Significance of Beta-Band Oscillations in Autism Spectrum Disorders During Motor Response Inhibition Tasks: A MEG Study. Brain Topogr., 33(3), 355–374. PMID:32303950, doi:10.1007/s10548-020-00765-6.

In Autism Spectrum Disorders (ASD), impaired response inhibition and lack of adaptation are hypothesized to underlie core ASD symptoms, such as social communication and repetitive, stereotyped behavior. Thus, the aim of the present study was to compare neural correlates of inhibition, post-error adaptation, and reaction time variability in ASD and neuro-typical control (NTC) participants by investigating possible differences in error-related changes of oscillatory MEG activity. Twelve male NTC (mean age 20.3 ± 3.7) and fourteen male patients with ASD (mean age 17.8 ± 2.9) were included in the analysis. Subjects with ASD showed increased error-related reaction time variability. MEG analysis revealed decreased beta power in the ASD group in comparison to the NTC group over the centro-parietal channels in both, the pre-stimulus and post-response interval. In the ASD group, mean centro-parietal beta power negatively correlated with dimensional autism symptoms. In both groups, false alarms were followed by an early increase in temporo-frontal theta to alpha power; and by a later decrease in alpha to beta power at central and posterior sensors. Single trial correlations were additionally studied in the ASD group, who showed a positive correlation of pre-stimulus beta power with post-response theta, alpha, and beta power, particularly after hit trials. On a broader scale, the results deliver important insights into top-down control deficits that may relate to core symptoms observed in ASD.

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.

Seethaler, B., Basrai, M., Vetter, W., Lehnert, K., …, Siniatchkin, M., …, & Bischoff, S. C. (2020). Fatty acid profiles in erythrocyte membranes following the Mediterranean diet – data from a multicenter lifestyle intervention study in women with hereditary breast cancer (LIBRE). Clin. Nutr., 39(8), 2389–2398. PMID:31735538, doi:10.1016/j.clnu.2019.10.033.

BACKGROUND & AIMS: Evidence-based concepts to prevent breast cancer in women with BRCA1/2 mutations are limited. Adherence to a Mediterranean diet (MedD) has been associated with a lower risk for breast cancer, possibly due to a favorable fatty acid (FA) intake. Here, we studied in an at-risk population the effect of a lifestyle intervention that included the MedD on FA composition in red blood cell membranes (RBCM). METHODS: Data derived from the German multicenter trial LIBRE, from which 68 women were randomized into an intervention group (IG) trained for MedD and increased physical activity for 12 months, and a usual care control group (CG). Adherence to the diet was assessed after 3 and 12 months using the validated Mediterranean Diet Adherence Screener (MEDAS) and a food frequency questionnaire. RBCM FA were analyzed by gas chromatography with mass spectrometry. RESULTS: The MEDAS was increased in both groups after 3 months (IG: P < 0.001; CG: P = 0.004), and remained increased only in the IG after 12 months (P < 0.001). The food frequency questionnaire revealed an increased intake of omega-3 (n-3) FA at month 3 and month 12 in the IG (both P < 0.01), but not in the CG, in which intake of energy, protein and saturated FA decreased. In both groups n-6 FA in the RBCM decreased (P < 0.001), while n-9 FA increased (P < 0.001) and n-3 FA were unchanged. Women with higher consumption of fish had higher amounts of n-3 fatty acids in the RBCM. The MEDAS was inversely correlated with n-6 fatty acids. CONCLUSIONS: The RBCM FA composition was associated with dietetic parameters related to the MedD. Adherence to the MedD resulted in an altered, likely favorable FA composition. Our data suggest selected FA as biomarkers to monitor compliance to a dietetic intervention such as the MedD. CLINICAL TRIAL REGISTRY: The trial is registered at (reference: NCT02087592).

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.

Siehl, S., Robjant, K., & Crombach, A. (2020). Systematic review and meta-analyses of the long-term efficacy of narrative exposure therapy for adults, children and perpetrators. Psychother. Res., pp. 1–16. PMID:33205713, doi:10.1080/10503307.2020.1847345.

Objective: Narrative Exposure Therapy (NET) is a short-term trauma-focused intervention originally developed for treating survivors of war and torture. The neurobiological theoretical foundations of NET would suggest that the approach should have long term beneficial effects. We tested this assumption and also provided an extensive overview of all NET studies for adults, for children (KIDNET), and for perpetrators (Forensic Offender Rehabilitation NET; FORNET). Method: Following a systematic literature review, we conducted meta-analyses with all studies that had control conditions, and with all Randomized Controlled Trials (RCTs). We assessed between-groups short- (< 6 months) and long-term (≥ 6 months) effect sizes for symptoms of posttraumatic stress disorder (PTSD) and depression. Results: In a total of 56 studies from 30 countries comparing 1370 participants treated with NET to 1055 controls, we found large between group effect sizes regarding the reduction of PTSD symptoms in favor of NET. Analyses of RCTs with active controls yielded small to medium effect sizes in the short-term, and large effect sizes in the long-term. Conclusions: NET, KIDNET, and FORNET yield beneficial and sustainable treatment results for severely traumatized individuals living in adverse circumstances. Studies in highly developed health care systems comparing NET with other evidence-based trauma-focused interventions are needed.

Sierawska, A., Moliadze, V., Splittgerber, M., Rogge, A., Siniatchkin, M., & Buyx, A. (2020). First Epileptic Seizure and Initial Diagnosis of Juvenile Myoclonus Epilepsy (JME) in a Transcranial Direct Current Stimulation (tDCS) Study– Ethical Analysis of a Clinical case. Neuroethics, 13(3), 347–351. doi:10.1007/s12152-020-09444-6.

We discuss an epileptic incident in an undiagnosed 13-year old girl participating in a clinical study investigating the effects of transcranial direct current stimulation (tDCS) in healthy children and adolescents. This incident poses important research ethics questions with regard to study design, especially pertaining to screening and gaining informed consent. Potential benefits and problems of the incident also need to be considered. The ethical analysis of the case presented in this paper has been informed by an in-depth interview conducted after the incident with the child and the accompanying parent. We discuss the ethical implications of the epileptic incident, the need for improving screening procedures for studies with minors and for providing more effective communication. This case also underscores the problem of undetected teenage epilepsy in neuropsychological clinical studies and the necessity of raising more awareness of this issue. Since research in tDCS is an active and expanding field, we conclude with providing some recommendation that could ensure that future research on tDCS, or other therapies and neuro-interventions where there is a risk of triggering an epileptic seizure, take into account the specifics of teenage epilepsy and the need for more thorough provision of information during the process of gaining informed consent.

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.

Splittgerber, M.*, Japaridze, N.*, Sierawska, A., Gimenez, S., …, Siniatchkin, M., & Moliadze, V. (2020). First generalized tonic clonic seizure in the context of pediatric tDCS – A case report. Neurophysiol. Clin., 50(1), 69–72. PMID:31848082, doi:10.1016/j.neucli.2019.11.002.
Splittgerber, M., Suwelack, J. H., Kadish, N. E.*, & Moliadze, V.*. (2020). The Effects of 1 mA tACS and tRNS on Children/Adolescents and Adults: Investigating Age and Sensitivity to Sham Stimulation. Neural Plast., 2020, 1–14. PMID:32855633, doi:10.1155/2020/8896423.

The aim of this study was to investigate the effect of transcranial random noise (tRNS) and transcranial alternating current (tACS) stimulation on motor cortex excitability in healthy children and adolescents. Additionally, based on our recent results on the individual response to sham in adults, we explored this effect in the pediatric population. We included 15 children and adolescents (10–16 years) and 28 adults (20–30 years). Participants were stimulated four times with 20 Hz and 140 Hz tACS, tRNS, and sham stimulation (1 mA) for 10 minutes over the left M1 HAND . Single-pulse MEPs (motor evoked potential), short-interval intracortical inhibition, and facilitation were measured by TMS before and after stimulation (baseline, 0, 30, 60 minutes). We also investigated aspects of tolerability. According to the individual MEPs response immediately after sham stimulation compared to baseline (Wilcoxon signed-rank test), subjects were regarded as responders or nonresponders to sham. We did not find a significant age effect. Regardless of age, 140 Hz tACS led to increased excitability. Incidence and intensity of side effects did not differ between age groups or type of stimulation. Analyses on responders and nonresponders to sham stimulation showed effects of 140 Hz, 20 Hz tACS, and tRNS on single-pulse MEPs only for nonresponders. In this study, children and adolescents responded to 1 mA tRNS and tACS comparably to adults regarding the modulation of motor cortex excitability. This study contributes to the findings that noninvasive brain stimulation is well tolerated in children and adolescents including tACS, which has not been studied before. Finally, our study supports a modulating role of sensitivity to sham stimulation on responsiveness to a broader stimulation and age range.

Splittgerber, M., Salvador, R., Brauer, H., Breitling-Ziegler, C., …, Moliadze, V.*, & Siniatchkin, M.*. (2020). Individual Baseline Performance and Electrode Montage Impact on the Effects of Anodal tDCS Over the Left Dorsolateral Prefrontal Cortex. Front. Hum. Neurosci., 14. doi:10.3389/fnhum.2020.00349.
Wagner, K., Gau, K., Metternich, B., Geiger, M. J., …, Kadish, N. E., …, & Foit, N. A. (2020). Effects of hippocampus-sparing resections in the temporal lobe: Hippocampal atrophy is associated with a decline in memory performance. Epilepsia, 61(4), 725–734. PMID:32162320, doi:10.1111/epi.16473.

Objective: In patients with temporal lobe epilepsy (TLE) with a nonlesional and nonepileptogenic hippocampus (HC), in order to preserve functionally intact brain tissue, the HC is not resected. However, some patients experience postoperative memory decline, possibly due to disruption of the extrahippocampal memory network and secondary hippocampal volume (HV) loss. The purpose of this study was to determine the extent of hippocampal atrophy ipsilateral and contralateral to the side of the surgery and its relation to memory outcomes. Methods: Hippocampal volume and verbal as well as visual memory performance were retrospectively examined in 55 patients (mean age ± standard deviation [SD] 30 ± 15 years, 25 female, 31 left) before and 5 months after surgery within the temporal lobe that spared the entire HC. HV was extracted based on prespecified templates, and resection volumes were also determined. Results: HV loss was found both ipsilateral and contralateral to the side of surgery (P <.001). Postoperative left HV loss was a significant predictor of postoperative verbal memory deterioration after left-sided surgery (P <.01). Together with the preoperative verbal memory performance, postoperative left HV explained almost 60% of the variance (P <.0001). However, right HV was not a clear predictor of visual memory performance. Larger resection volumes were associated with smaller postoperative HV, irrespective of side of surgery (left: P <.05, right: P <.01). Significance: A disruption of the memory network by any resection within the TL, especially within the language-dominant hemisphere, may lead to HC atrophy and memory decline. These findings may further improve the counseling of patients concerning their postoperative memory outcome before TL resections sparing the entire HC.

Wu, Y., Hall, A. S. M., Siehl, S., Grafman, J., & Krueger, F. (2020). Neural Signatures of Gender Differences in Interpersonal Trust. Front. Hum. Neurosci., 14, 225. PMID:32612518, doi:10.3389/fnhum.2020.00225.

Trust plays a critical role in nearly every aspect of social life. Parental investment theory and social role theory predict that women trust less than men due to a higher sensitivity to risk and betrayal, while men trust more than women to maximize resources and to signal their willingness to lose something. However, the underlying neuropsychological underpinnings for this gender difference are still obscure. In this study, we used functional magnetic resonance imaging (fMRI) to investigate the neural signatures of gender differences in trust by simultaneously scanning 11 male and 11 female same-gender, fixed dyads who played a multi-round binary trust game with varying levels of payoff (low/moderate/high) as an indicator of social risk. Our results showed that men trusted more than women and payoff level moderated the effect of gender on trust. While men trusted the same at all payoff levels, women trusted less with higher payoff levels. This pattern was supported by our neuroimaging finding: men showed a higher activation in the left inferior frontal gyrus (ventrolateral prefrontal cortex) and right precuneus than women, indicating that men exert more effort to inhibit the information of payoff levels and to use self-referencing to infer the strategies of partners with the goal of maximizing profit. Furthermore, men showed equivalent activation in the subgenual anterior cingulate cortex across payoff levels, whereas women showed a decreased activation with increasing payoff level - indicating decreased group bonding with higher risk in women. In conclusion, our results imply that women are more sensitive to social risk while trusting, which has implications for financial interactions, interpersonal relationships, and social involvement.

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.


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.

Few studies have investigated the link between putative biomarkers of attention-deficit/hyperactivity disorder (ADHD) symptomatology and genetic risk for ADHD. To address this, we investigate the degree to which ADHD symptomatology is associated with white matter microstructure and cerebral cortical thickness in a large population-based sample of adolescents. Critically, we then test the extent to which multimodal correlates of ADHD symptomatology are related to ADHD polygenic risk score (PRS). Neuroimaging, genetic, and behavioral data were obtained from the IMAGEN study. A dimensional ADHD composite score was derived from multi-informant ratings of ADHD symptomatology. Using tract-based spatial statistics, whole brain voxel-wise regressions between fractional anisotropy (FA) and ADHD composite score were calculated. Local cortical thickness was regressed on ADHD composite score. ADHD PRS was based on a very recent genome-wide association study, and calculated using PRSice. ADHD composite score was negatively associated with FA in several white matter pathways, including bilateral superior and inferior longitudinal fasciculi (p < 0.05, corrected). ADHD composite score was negatively associated with orbitofrontal cortical thickness (p < 0.05, corrected). The ADHD composite score was correlated with ADHD PRS (p < 0.001). FA correlates of ADHD symptomatology were significantly associated with ADHD PRS, whereas cortical thickness correlates of ADHD symptomatology were unrelated to ADHD PRS. Variation in hyperactive/inattentive symptomatology was associated with white matter microstructure, which, in turn, was related to ADHD PRS. Results suggest that genetic risk for ADHD symptomatology may be tied to biological processes affecting white matter microstructure.

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.

BACKGROUND Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. METHODS Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. RESULTS Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. CONCLUSIONS These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

Deco, G., Cruzat, J., Cabral, J., Tagliazucchi, E., …, & Kringelbach, M. L. (2019). Awakening: Predicting external stimulation to force transitions between different brain states. Proc. Natl. Acad. Sci., 116(36), 18088–18097. doi:10.1073/pnas.1905534116.

A fundamental problem in systems neuroscience is how to force a transition from one brain state to another by external driven stimulation in, for example, wakefulness, sleep, coma, or neuropsychiatric diseases. This requires a quantitative and robust definition of a brain state, which has so far proven elusive. Here, we provide such a definition, which, together with whole-brain modeling, permits the systematic study in silico of how simulated brain stimulation can force transitions between different brain states in humans. Specifically, we use a unique neuroimaging dataset of human sleep to systematically investigate where to stimulate the brain to force an awakening of the human sleeping brain and vice versa. We show where this is possible using a definition of a brain state as an ensemble of “metastable substates,” each with a probabilistic stability and occurrence frequency fitted by a generative whole-brain model, fine-tuned on the basis of the effective connectivity. Given the biophysical limitations of direct electrical stimulation (DES) of microcircuits, this opens exciting possibilities for discovering stimulation targets and selecting connectivity patterns that can ensure propagation of DES-induced neural excitation, potentially making it possible to create awakenings from complex cases of brain injury.

El Sayed Hussein Jomaa, M., Van Bogaert, P., Jrad, N., Kadish, N. E., …, Siniatchkin, M., …, & Humeau-Heurtier, A. (2019). Multivariate improved weighted multiscale permutation entropy and its application on EEG data. Biomed. Signal Process. Control, 52, 420–428. doi:10.1016/j.bspc.2018.08.004.

This paper introduces an entropy based method that measures complexity in non-stationary multivariate signals. This method, called Mutivariate Improved Weighted Multiscale Permutation Entropy (mvIWMPE), has two main advantages: (i) it shows lower variance for the results when applied on a wide range of multivariate signals; (ii) it has good accuracy quantifying complexity of different recorded states in signals and hence discriminating them. mvIWMPE is based on two previously introduced permutation entropy algorithms, Improved Multiscale Permutation Entropy (IMPE) and Multivariate Weighted Multiscale Permutation Entropy (mvWMPE). It combines the concept of coarse graining from IMPE and the introduction of the weight of amplitudes of the signals from mvWMPE. mvIWMPE was validated on both synthetic and human electroencephalographic (EEG) signals. Several synthetic signals were simulated: mixtures of white Gaussian noise (WGN) and pink noise, chaotic and convergent Lorenz system signals, stochastic and deterministic signals. As for real signals, resting-state EEG recorded in healthy and epileptic children during eyes closed and eyes open sessions were analyzed. Our method was compared to multivariate multiscale, multivariate weighted multiscale and multivariate improved multiscale permutation entropy methods. Performance on synthetic as well as on EEG signals showed more undeviating results and higher ability for mvIWMPE discriminating different states of signals (chaotic vs convergent, WGN vs pink noise, stochastic vs deterministic simulated signals, and eyes open vs eyes closed EEG signals). We herein proposed an efficient method to measure the complexity of multivariate non-stationary signals. Experimental results showed the accuracy and the robustness (in terms of variance) of the method.

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.

Friedrich, R.-M., Zabel, S., Galka, A., Lukat, N., …, Siniatchkin, M., & Faupel, F. (2019). Magnetic particle mapping using magnetoelectric sensors as an imaging modality. Sci. Rep., 9(1), 2086. PMID:30765847, doi:10.1038/s41598-018-38451-0.

Magnetic nanoparticles (MNPs) are a hot topic in the field of medical life sciences, as they are highly relevant in diagnostic applications. In this regard, a large variety of novel imaging methods for MNP in biological systems have been invented. In this proof-of-concept study, a new and novel technique is explored, called Magnetic Particle Mapping (MPM), using resonant magnetoelectric (ME) sensors for the detection of MNPs that could prove to be a cheap and efficient way to localize the magnetic nanoparticles. The simple and straightforward setup and measurement procedure includes the detection of higher harmonic excitations of MNP ensembles. We show the feasibility of this approach by building a measurement setup particularly suited to exploit the inherent sensor properties. We measure the magnetic response from 2D MNP distributions and reconstruct the distribution by solving the inverse problem. Furthermore, biological samples with magnetically labeled cells were measured and reconstruction of the distribution was compared with light microscope images. Measurement results suggest that the approach presented here is promising for MNP localization.

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.

Haselbeck, C., Niederberger, U., Gubi-Kelm, S., Jahn, F., …, & Siniatchkin, M. (2019). Secure attachment style appears to compensate for the effect of prenatal maternal distress regarding difficult infant temperament development. Z. Kinder. Jugendpsychiatr. Psychother., 47(3), 239–251. PMID:30080118, doi:10.1024/1422-4917/a000606.

Objective: Secure attachment style is a known protective factor regarding psychopathological development. The infant's attachment style, which is developed during the first two years of life, is therefore considered a moderating factor on the association between prenatal maternal distress and child temperament development which has repeatedly been reported in previous studies. Method: In this longitudinal study on a new sample of 51 mother-child-dyads, reported maternal distress and maternal empathy were assessed during pregnancy. Infant temperament and motor development were assessed at 12 months, while additionally controlling for the infant's attachment style as a postnatal factor. Results: Infants with secure attachment style whose mothers had experienced higher prenatal distress showed slightly better gross motor development at the age of 12 months. No association could be found between prenatal maternal distress and infant temperament. Conclusions: The results support the view that secure attachment style in children is a protective factor and softens the effects of prenatal maternal distress on difficult temperament development.

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.

Kadish, N. E., Bast, T., Reuner, G., Wagner, K., …, & Ramantani, G. (2019). Epilepsy Surgery in the First 3 Years of Life: Predictors of Seizure Freedom and Cognitive Development. Neurosurgery, 84(6), E368—-E377. PMID:30137548, doi:10.1093/neuros/nyy376.

BACKGROUND: Although the majority of children undergoing epilepsy surgery are younger than 3 yr at epilepsy manifestation, only few actually receive surgical treatment in early childhood. Past studies have, however, suggested that earlier intervention may correlate with superior developmental outcomes. OBJECTIVE: To identify predictors for long-term seizure freedom and cognitive development following epilepsy surgery in the first 3 yr of life and determine the appropriate timing for surgical treatment in this age group. METHODS: We retrospectively analyzed the data of 48 consecutive children aged 1.1 ± 0.7 yr at surgery. RESULTS: Final surgeries comprised 52% hemispherotomies, 13% multilobar, and 35% intralobar resections. Etiology included cortical malformations in 71%, peri- or postnatal ischemic lesions in 13%, and benign tumor or tuberous sclerosis in 8% each. At last follow-up (median 4.3, range 1-14.3 yr), 60% of children remained seizure-free: 38% had discontinued antiepileptic drugs. Intralobar lesionectomy resulted more often in seizure control than multilobar or hemispheric surgery. Postsurgical seizure freedom was determined by the completeness of resection. Early postsurgical seizures were key markers of seizure recurrence. Presurgical adaptive and cognitive developmental status was impaired in 89% children. Longer epilepsy duration and larger lesion extent were detrimental to presurgical development, which, in turn, determined the postsurgical developmental outcome. CONCLUSION: Our study demonstrates that epilepsy surgery in very young children is safe as well as efficient regarding long-term seizure freedom and antiepileptic drug cessation in selected candidates. Longer epilepsy duration is the only modifiable predictor of impaired adaptive and cognitive development, thus supporting early surgical intervention.

Kortuem, V., Kadish, N. E., Siniatchkin, M., & Moliadze, V. (2019). Efficacy of tRNS and 140 Hz tACS on motor cortex excitability seemingly dependent on sensitivity to sham stimulation. Exp. Brain Res., 237(11), 2885–2895. PMID:31482197, doi:10.1007/s00221-019-05640-w.

This study investigates the effect of corticospinal excitability during sham stimulation on the individual response to transcranial non-invasive brain stimulation (tNIBS). Thirty healthy young adults aged 24.2 ± 2.8 S.D. participated in the study. Sham, as well as 1 mA of tRNS and 140 Hz tACS stimulation were applied for 10 min each at different sessions. The effect of each stimulation type was quantified by recording TMS-induced, motor evoked potentials (MEPs) before (baseline) and at fixed time points after stimulation (T0, T30, T60 min.). According to the individual response to sham stimulation at T0 in comparison to baseline MEPs, subjects were regarded as responder or non-responder to sham. Following, MEPs at T0, T30 and T60 after verum or sham stimulation were assessed with a repeated measures ANOVA with the within-subject factor stimulation (sham, tRNS, 140 Hz tACS) and the between-subjects factor group (responder vs non-responder). We found that individuals who did not show immediately changes in excitability in sham stimulation sessions were the ones who responded to active stimulation conditions. On the other hand, individuals who responded to sham condition, by either increases or decreases in MEPS, did not respond to active verum stimulation. This result suggests that the presence or lack of responses to sham stimulation can provide a marker for how individuals will respond to tRNS/tACS and thus provide an explanation for the variability in interindividual response. The results of this study draw attention to the general reactivity of the brain, which can be taken into account when planning future studies using tNIBS.

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.

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..

Mégevand, P., Hamid, L., Dümpelmann, M., & Heers, M. (2019). New horizons in clinical electric source imaging. Zeitschrift für Epileptol., 32(3), 187–193. doi:10.1007/s10309-019-0258-6.
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.

Moliadze, V., Sierau, L., Lyzhko, E., Stenner, T., …, Siniatchkin, M., & Hartwigsen, G. (2019). After-effects of 10 Hz tACS over the prefrontal cortex on phonological word decisions. Brain stimulation, 12(6), 1464–1474. PMID:31278060, doi:10.1016/j.brs.2019.06.021.

Introduction: Previous work in the language domain has shown that 10 Hz rTMS of the left or right posterior inferior frontal gyrus (pIFG) in the prefrontal cortex impaired phonological decision-making, arguing for a causal contribution of the bilateral pIFG to phonological processing. However, the neurophysiological correlates of these effects are unclear. The present study addressed the question whether neural activity in the prefrontal cortex could be modulated by 10 Hz tACS and how this would affect phonological decisions. Methods: In three sessions, 24 healthy participants received tACS at 10 Hz or 16.18 Hz (control frequency) or sham stimulation over the bilateral prefrontal cortex before task processing. Resting state EEG was recorded before and after tACS. We also recorded EEG during task processing. Results: Relative to sham stimulation, 10 Hz tACS significantly facilitated phonological response speed. This effect was task-specific as tACS did not affect a simple control task. Moreover, 10 Hz tACS significantly increased theta power during phonological decisions. The individual increase in theta power was positively correlated with the behavioral facilitation after 10 Hz tACS. Conclusion: Our results show a facilitation of phonological decisions after 10 Hz tACS over the bilateral prefrontal cortex. This might indicate that 10 Hz tACS increased task-related activity in the stimulated area to a level that was optimal for phonological performance. The significant correlation with the individual increase in theta power suggests that the behavioral facilitation might be related to increased theta power during language processing.

Moontaha, S., Galka, A., Siniatchkin, M., Scharlach, S., …, & Meurer, T. (2019). SVD Square-root Iterated Extended Kalman Filter for Modeling of Epileptic Seizure Count Time Series with External Inputs. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. IEEE Eng. Med. Biol. Soc. Annu. Int. Conf., 2019, 616–619. PMID:31945973, doi:10.1109/EMBC.2019.8857159.

In this paper a nonlinear filtering algorithm for count time series is developed that takes the non-negativity of the data into account and preserves positive definiteness of the covariance matrices of the model. For this purpose, a recently proposed variant of Kalman Filtering based on Singular Value Decomposition is incorporated into Iterative Extended Kalman Filtering, in order to estimate the states of a nonlinear state space model. The resulting algorithm is applied to the evaluation and design of therapies for patients suffering from Myoclonic Astatic Epilepsy, employing time series of daily seizure rate. The analysis provides a decision whether for a specific patient a particular anti-epileptic drug is increasing or reducing the seizure rate. Through a simulation study the proposed algorithm is validated. Additionally, for clinical data results obtained by the proposed algorithm are compared with the results from a Cox-Stuart trend test as well as with the visual assessment of experienced pediatric epileptologists.

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.

Muthuraman, M.*, Moliadze, V.*, Boecher, L., Siemann, J., …, & Siniatchkin, M. (2019). Multimodal alterations of directed connectivity profiles in patients with attention-deficit/hyperactivity disorders. Sci. Rep. PMID:31882672, doi:10.1038/s41598-019-56398-8.

Functional and effective connectivity measures for tracking brain region interactions that have been investigated using both electroencephalography (EEG) and magnetoencephalography (MEG) bringing up new insights into clinical research. However, the differences between these connectivity methods, especially at the source level, have not yet been systematically studied. The dynamic characterization of coherent sources and temporal partial directed coherence, as measures of functional and effective connectivity, were applied to multimodal resting EEG and MEG data obtained from 11 young patients (mean age 13.2 ± 1.5 years) with attention-deficit/hyperactivity disorder (ADHD) and age-matched healthy subjects. Additionally, machine-learning algorithms were applied to the extracted connectivity features to identify biomarkers differentiating the two groups. An altered thalamo-cortical connectivity profile was attested in patients with ADHD who showed solely information outflow from cortical regions in comparison to healthy controls who exhibited bidirectional interregional connectivity in alpha, beta, and gamma frequency bands. We achieved an accuracy of 98% by combining features from all five studied frequency bands. Our findings suggest that both types of connectivity as extracted from EEG or MEG are sensitive methods to investigate neuronal network features in neuropsychiatric disorders. The connectivity features investigated here can be further tested as biomarkers of ADHD.

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.

Sierawska, A., Prehn-Kristensen, A., Moliadze, V., Krauel, K., …, Siniatchkin, M., & Buyx, A. (2019). Unmet Needs in Children With Attention Deficit Hyperactivity Disorder—Can Transcranial Direct Current Stimulation Fill the Gap? Promises and Ethical Challenges. Front. Psychiatry, 10. doi:10.3389/fpsyt.2019.00334.

Attention deficit hyperactivity disorder (ADHD) is a disorder most frequently diagnosed in children and adolescents. Although ADHD can be effectively treated with psychostimulants, a significant proportion of patients discontinue treatment because of adverse events or insufficient improvement of symptoms. In addition, cognitive abilities that are frequently impaired in ADHD are not directly targeted by medication. Therefore, additional treatment options, especially to improve cognitive abilities, are needed. Because of its relatively easy application, well-established safety, and low cost, transcranial direct current stimulation (tDCS) is a promising additional treatment option. Further research is needed to establish efficacy and to integrate this treatment into the clinical routine. In particular, limited evidence regarding the use of tDCS in children, lack of clear translational guidelines, and general challenges in conducting research with vulnerable populations pose a number of practical and ethical challenges to tDCS intervention studies. In this paper, we identify and discuss ethical issues related to research on tDCS and its potential therapeutic use for ADHD in children and adolescents. Relevant ethical issues in the tDCS research for pediatric ADHD center on safety, risk/benefit ratio, information and consent, labeling problems, and nonmedical use. Following an analysis of these issues, we developed a list of recommendations that can guide clinicians and researchers in conducting ethically sound research on tDCS in pediatric ADHD.

Siniatchkin, M., & Van Bogaert, P. (2019). Pathophysiology of encephalopathy related to continuous spike and waves during sleep: the contribution of neuroimaging. Epileptic Disord., 21(S1), 48–53. PMID:31149901, doi:10.1684/epd.2019.1057.

In the last three decades, studies on functional neuroimaging have helped us to understand pathophysiological mechanisms responsible for electro-clinical patterns associated with epileptic encephalopathies with continuous spikes and waves during slow sleep (ECSWS). MEG and EEG source reconstruction have revealed sources of pathological brain activity associated with epileptiform discharges in the perisylvian region pointing to the significance of this brain area for ECSWS. PET studies have revealed areas of focal hypermetabolism in perisylvian, superior temporal and inferior parietal regions as well as central cortices which were related to epileptic activity. The widespread hypometabolism in regions that belong to the default network (prefrontal and posterior cingulate cortices, parahippocampal gyrus and precuneus) was interpreted as remote inhibition following epileptic activity, which could contribute to cognitive deficits in affected individuals. Note that the described metabolic changes were functional and disappeared after successful treatment and recovery of ECSWS and were found in both sleep and wakefulness which may account for cognitive deficits in patients during the day. EEG-fMRI studies have revealed a functional fingerprint of epileptic encephalopathy: significant positive BOLD signal changes were identified in the perisylvian regions, prefrontal cortex and anterior cingulate as well as thalamus and negative BOLD signal changes in the regions of the default mode network. The pattern of activation represents a propagation of epileptic activity specific to encephalopathy, which is independent of etiology and type of seizure associated with ECSWS. In summary, methods of neuroimaging have shed light on pathogenic mechanisms of ECSWS which may account for a number of clinical phenomena associated with this condition.

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