Henrik Walter

YNICL Journal 2025 Journal Article

Brain age gap reduction following exercise mirrors clinical improvements in schizophrenia spectrum disorders

• Deniz Yilmaz
• Sergi Papiol
• Daniel Keeser
• James H. Cole
• Berend Malchow
• Henrik Walter
• Andreas Meyer-Lindenberg
• Dusan Hirjak

Schizophrenia spectrum disorders (SSD) are associated with accelerated brain aging, reflected in an increased brain age gap. This gap serves as a biomarker, indicating poorer brain health, cognitive deficits, and greater severity in specific symptom domains. Exercise holds promise as an adjunct therapy to mitigate these deficits by potentially promoting brain recovery. However, the extent of overall improvements in brain health following exercise, along with their predictors and relationships to symptom clusters, are yet to be determined. This study examined the brain age gap metric as a quantitative indicator of brain recovery in response to exercise. To achieve this, we aggregated data from two randomized controlled trials, analyzing baseline (n = 134) and 3- or 6-month post-exercise (n = 46) data from individuals with SSD. Our findings revealed that patients with a higher baseline body mass index (BMI) demonstrated greater brain recovery, as evidenced by a reduced brain age gap post-exercise. Furthermore, changes in the brain age gap were associated with improvements in negative symptoms and cognition, suggesting that reductions in brain-predicted age may reflect symptom relief, particularly in domains beyond positive symptoms. These results underscore the importance of BMI in brain health, support using the brain age gap as a surrogate marker for tracking clinically relevant brain recovery, and highlight the need for stratified interventions and combined lifestyle modifications to enhance outcomes in SSD.

YNIMG Journal 2025 Journal Article

Image-based meta- and mega-analysis (IBMMA): A unified framework for large-scale, multi-site, neuroimaging data analysis

• Nick Steele
• Ashley A. Huggins
• Rajendra A. Morey
• Ahmed Hussain
• Courtney Russell
• Benjamin Suarez-Jimenez
• Elena Pozzi
• Hadis Jameei

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA successfully analyzed a large-n dataset of several thousand participants and revealed findings in brain regions that some traditional software overlooked due to missing voxel-data resulting in gaps in brain coverage. IBMMA has the potential to accelerate discoveries in neuroscience and enhance the clinical utility of neuroimaging findings.

YNIMG Journal 2023 Journal Article

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium

• Xi Zhu
• Yoojean Kim
• Orren Ravid
• Xiaofu He
• Benjamin Suarez-Jimenez
• Sigal Zilcha-Mano
• Amit Lazarov
• Seonjoo Lee

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

YNICL Journal 2023 Journal Article

Uncontrolled eating and sensation-seeking partially explain the prediction of future binge drinking from adolescent brain structure

• Roshan Prakash Rane
• Milena Philomena Maria Musial
• Anne Beck
• Michael Rapp
• Florian Schlagenhauf
• Tobias Banaschewski
• Arun L.W. Bokde
• Marie-Laure Paillère Martinot

Binge drinking behavior in early adulthood can be predicted from brain structure during early adolescence with an accuracy of above 70%. We investigated whether this accurate prospective prediction of alcohol misuse behavior can be explained by psychometric variables such as personality traits or mental health comorbidities in a data-driven approach. We analyzed a subset of adolescents who did not have any prior binge drinking experience at age 14 (IMAGEN dataset, n = 555, 52.61% female). Participants underwent structural magnetic resonance imaging at age 14, binge drinking assessments at ages 14 and 22, and psychometric questionnaire assessments at ages 14 and 22. We derived structural brain features from T1-weighted magnetic resonance and diffusion tensor imaging. Using Machine Learning (ML), we predicted binge drinking (age 22) from brain structure (age 14) and used counterbalancing with oversampling to systematically control for 110 + variables from a wide range of social, personality, and other psychometric characteristics potentially associated with binge drinking. We evaluated if controlling for any variable resulted in a significant reduction in ML prediction accuracy. Sensation-seeking (-13.98 ± 1.68%), assessed via the Substance Use Risk Profile Scale at age 14, and uncontrolled eating (-13.98 ± 3.28%), assessed via the Three-Factor-Eating-Questionnaire at age 22, led to significant reductions in mean balanced prediction accuracy upon controlling for them. Thus, sensation-seeking and binge eating could partially explain the prediction of future binge drinking from adolescent brain structure. Our findings suggest that binge drinking and binge eating at age 22 share common neurobiological precursors discovered by the ML model. These neurobiological precursors seem to be associated with sensation-seeking at age 14. Our results facilitate early detection of increased risk for binge drinking and inform future clinical research in trans-diagnostic prevention approaches for adolescent alcohol misuse.

YNIMG Journal 2022 Journal Article

A comparison of methods to harmonize cortical thickness measurements across scanners and sites

• Delin Sun
• Gopalkumar Rakesh
• Courtney C. Haswell
• Mark Logue
• C. Lexi Baird
• Erin N. O'Leary
• Andrew S. Cotton
• Hong Xie

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1, 340 cases with posttraumatic stress disorder (PTSD) (6. 2–81. 8 years old) and 2, 057 trauma-exposed controls without PTSD (6. 3–85. 2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2(3) = 63. 704, p < 0. 001) as well as case-control differences in age-related cortical thinning (Χ 2(3) = 12. 082, p = 0. 007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2(3) = 9. 114, p = 0. 028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0. 001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0. 001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0. 001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0. 001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0. 001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

YNIMG Journal 2021 Journal Article

NBS-Predict: A prediction-based extension of the network-based statistic

• Emin Serin
• Andrew Zalesky
• Adu Matory
• Henrik Walter
• Johann D. Kruschwitz

Graph models of the brain hold great promise as a framework to study functional and structural brain connectivity across scales and species. The network-based statistic (NBS) is a well-known tool for performing statistical inference on brain graphs, which controls the family-wise error rate in a mass univariate analysis by combining the cluster-based permutation technique and the graph-theoretical concept of connected components. As the NBS is based on group-level inference statistics, it does not inherently enable informed decisions at the level of individuals, which is, however, necessary for the realm of precision medicine. Here we introduce NBS-Predict, a new approach that combines the powerful features of machine learning (ML) and the NBS in a user-friendly graphical user interface (GUI). By combining ML models with connected components in a cross-validation (CV) structure, the new methodology provides a fast and convenient tool to identify generalizable neuroimaging-based biomarkers. The purpose of this paper is to (i) introduce NBS-Predict and evaluate its performance using two sets of simulated data with known ground truths, (ii) demonstrate the application of NBS-Predict in a real case-control study, including resting-state functional magnetic resonance imaging (rs-fMRI) data acquired from patients with schizophrenia, (iii) evaluate NBS-Predict using rs-fMRI data from the Human Connectome Project 1200 subjects release. We found that: (i) NBS-Predict achieved good statistical power on two sets of simulated data; (ii) NBS-Predict classified schizophrenia with an accuracy of 90% using subjects' functional connectivity matrices and identified a subnetwork with reduced connections in the group with schizophrenia, mainly comprising brain regions localized in frontotemporal, visual, and motor areas, as well as in the subcortex; (iii) NBS-Predict also predicted general intelligence scores from resting-state fMRI connectivity matrices with a prediction score of r = 0.2 and identified a large-scale subnetwork associated with general intelligence. Overall results showed that NBS-Predict performed comparable to or better than pre-existing feature selection algorithms (lasso, elastic net, top 5%, p-value thresholding) and connectome-based predictive modeling (CPM) in terms of identifying relevant features and prediction accuracy.

YNIMG Journal 2021 Journal Article

Similarity and stability of face network across populations and throughout adolescence and adulthood

• Zhijie Liao
• Tobias Banaschewski
• Arun L.W. Bokde
• Sylvane Desrivières
• Herta Flor
• Antoine Grigis
• Hugh Garavan
• Penny Gowland

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.

YNIMG Journal 2020 Journal Article

Brain structure and habitat: Do the brains of our children tell us where they have been brought up?

• Simone Kühn
• Tobias Banaschewski
• Arun L.W. Bokde
• Christian Büchel
• Erin Burke Quinlan
• Sylvane Desrivières
• Herta Flor
• Antoine Grigis

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.

YNIMG Journal 2020 Journal Article

Self-control and interoception: Linking the neural substrates of craving regulation and the prediction of aversive interoceptive states induced by inspiratory breathing restriction

• Henrik Walter
• Anne Kausch
• Lena Dorfschmidt
• Lea Waller
• Narges Chinichian
• Ilya Veer
• Kevin Hilbert
• Ulrike Lüken

Following the interoceptive inference framework, we set out to replicate our previously reported association of self-control and interoceptive prediction and strived to investigate the neural underpinnings subserving the relationship between self-control and aversive interoceptive predictive models. To this end, we used fMRI and a within-subject design including an inspiratory breathing-load task to examine the prediction of aversive interoceptive perturbation and a craving-regulation for palatable foods task to measure self-control. In this current study, we could successfully replicate previous effects with an independent sample (n ​= ​39) and observed that individuals who ‘over-estimated’ their upcoming interoceptive state with respect to experienced dyspnea (i. e. , anticipated versus experienced) were more effective in the down-regulation of craving using negative future-thinking strategies. These individuals, again, obtained higher scores on a measure of trait self-control, i. e. self-regulation to achieve long-term goals. On a neural level, we found evidence that the anterior insula (AI) and the presupplementary motor area (preSMA), which were recruited in both tasks, partly accounted for these effects. Specifically, levels of AI activation during the anticipation of the aversive interoceptive state (breathing restriction) were associated with self-controlled behavior in the craving task, whereas levels of interoceptive prediction during the breathing task were conversely associated with activation in preSMA during the down-regulation of craving, whose anticipatory activity was correlated with self-control success. Moreover, during the self-control task, levels of interoceptive prediction were associated with connectivity in a spatially distributed network including among other areas the insula and regions of cognitive control, while during the interoceptive prediction task, levels of self-control were associated with connectivity in a spatially distributed network including among other regions the insula and preSMA. In sum, these findings consolidate the notion that self-control is directly linked to interoceptive inference and highlight the contribution of AI and preSMA as candidate regions underlying this relationship possibly creating processing advantages in self-control situations referring to the prediction of future internal states.

YNIMG Journal 2020 Journal Article

Sex effects on structural maturation of the limbic system and outcomes on emotional regulation during adolescence

• Pauline Bezivin Frere
• Nora C. Vetter
• Eric Artiges
• Irina Filippi
• Rubén Miranda
• Hélène Vulser
• Marie-Laure Paillère-Martinot
• Veronika Ziesch

Though adolescence is a time of emerging sex differences in emotions, sex-related differences in the anatomy of the maturing brain has been under-explored over this period. The aim of this study was to investigate whether puberty and sexual differentiation in brain maturation could explain emotional differences between girls and boys during adolescence. We adapted a dedicated longitudinal pipeline to process structural and diffusion images from 335 typically developing adolescents between 14 and 16 years. We used voxel-based and Regions of Interest approaches to explore sex and puberty effects on brain and behavioral changes during adolescence. Sexual differences in brain maturation were characterized by amygdala and hippocampal volume increase in boys and decrease in girls. These changes were mediating the sexual differences in positive emotional regulation as illustrated by positive attributes increase in boys and decrease in girls. Moreover, the differential maturation rates between the limbic system and the prefrontal cortex highlighted the delayed maturation in boys compared to girls. This is the first study to show the sex effects on the differential cortico/subcortical maturation rates and the interaction between sex and puberty in the limbic system maturation related to positive attributes, reported as being protective from emotional disorders.

YNIMG Journal 2020 Journal Article

The empirical replicability of task-based fMRI as a function of sample size

• Han Bossier
• Sanne P. Roels
• Ruth Seurinck
• Tobias Banaschewski
• Gareth J. Barker
• Arun L.W. Bokde
• Erin Burke Quinlan
• Sylvane Desrivières

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.

YNICL Journal 2019 Journal Article

Adolescent binge drinking disrupts normal trajectories of brain functional organization and personality maturation

• Hongtao Ruan
• Yunyi Zhou
• Qiang Luo
• Gabriel H. Robert
• Sylvane Desrivières
• Erin Burke Quinlan
• ZhaoWen Liu
• Tobias Banaschewski

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.

YNICL Journal 2019 Journal Article

Expectation of sexual images of adults and children elicits differential dorsal anterior cingulate cortex activation in pedophilic sexual offenders and healthy controls

• Inka Ristow
• Jens Foell
• Christian Kärgel
• Viola Borchardt
• Shijia Li
• Dominik Denzel
• Joachim Witzel
• Krasimira Drumkova

BACKGROUND: Pedophilic disorder is characterized by increased sexual interest towards children, with comparatively lesser interest towards adults. In real life, the behavior of subjects with pedophilic disorder is shaped by evaluative processes in response to sexually relevant cues. Therefore, brain activation during anticipation of sexually relevant cues is of potential interest. Whereas previous research demonstrated reduced activation when viewing adult (non-preferred) sexual stimuli in pedophilic sex offenders (PSOs), it is not known if anticipation of preferred versus unpreferred stimuli will elicit differential brain activation. METHODS: Two fMRI studies (1.5 and 7 Tesla) were conducted in separate samples, each with 26 subjects (13/13 PSOs/controls) to assess brain activity during expectancy of subsequent adult (non-preferred) sexual stimuli. In the second study (7 Tesla) additionally child (preferred) cues were presented. RESULTS: As predicted, expectancy of adult sexual stimuli generated smaller dorsal anterior cingulate cortex (dACC) activation in PSOs in both studies, driven by stronger activation during expectancy of adult erotic stimuli in non-pedophilic controls (HCs). In the second study, PSOs showed significantly increased activations in dACC during expectancy of child stimuli compared with expectancy of adult stimuli. This difference was significantly greater compared to the same contrast in HCs, thus demonstrating preference specificity of dACC activation. CONCLUSION: Our findings support the notion of decreased brain activation to adult cues in PSOs and preference specificity in neural response during expectancy of erotic stimuli. The localization of these cue reactivity differences in the salience network supports the interpretation that PSOs show abnormally increased preparatory activation even before relevant sexual stimuli are actually presented.

YNIMG Journal 2019 Journal Article

Quantifying performance of machine learning methods for neuroimaging data

• Lee Jollans
• Rory Boyle
• Eric Artiges
• Tobias Banaschewski
• Sylvane Desrivières
• Antoine Grigis
• Jean-Luc Martinot
• Tomáš Paus

Machine learning is increasingly being applied to neuroimaging data. However, most machine learning algorithms have not been designed to accommodate neuroimaging data, which typically has many more data points than subjects, in addition to multicollinearity and low signal-to-noise. Consequently, the relative efficacy of different machine learning regression algorithms for different types of neuroimaging data are not known. Here, we sought to quantify the performance of a variety of machine learning algorithms for use with neuroimaging data with various sample sizes, feature set sizes, and predictor effect sizes. The contribution of additional machine learning techniques – embedded feature selection and bootstrap aggregation (bagging) – to model performance was also quantified. Five machine learning regression methods – Gaussian Process Regression, Multiple Kernel Learning, Kernel Ridge Regression, the Elastic Net and Random Forest, were examined with both real and simulated MRI data, and in comparison to standard multiple regression. The different machine learning regression algorithms produced varying results, which depended on sample size, feature set size, and predictor effect size. When the effect size was large, the Elastic Net, Kernel Ridge Regression and Gaussian Process Regression performed well at most sample sizes and feature set sizes. However, when the effect size was small, only the Elastic Net made accurate predictions, but this was limited to analyses with sample sizes greater than 400. Random Forest also produced a moderate performance for small effect sizes, but could do so across all sample sizes. Machine learning techniques also improved prediction accuracy for multiple regression. These data provide empirical evidence for the differential performance of various machines on neuroimaging data, which are dependent on number of sample size, features and effect size.

YNIMG Journal 2018 Journal Article

Anticipating the good and the bad: A study on the neural correlates of bivalent emotion anticipation and their malleability via attentional deployment

• Johann D. Kruschwitz
• Lea Waller
• David List
• David Wisniewski
• Vera U. Ludwig
• Franziska Korb
• Uta Wolfensteller
• Thomas Goschke

In everyday life, we often deliberate about affective outcomes of decisions which can be described as ambivalent; i. e. positive and negative at the same time. For example, when looking forward to meet a dear friend at her/his favorite concert although one dislikes the music that is being performed. Thus, anticipation of bivalent emotions and their volitional regulation is an important ingredient of everyday choices. However, previous studies investigating neural substrates involved in anticipating emotional events mostly focused on anticipating either negative emotions (punishment) or positive emotions (reward) in isolation, thus inducing either of them separately. Furthermore, these studies rather focused on the effortful down-regulation of affect (i. e. reducing negative or positive affect), whereas such conflict situations may also require us to deploy attention on and thereby upregulate anticipated emotions in order to resolve a decision conflict (e. g. , by focusing on positive consequences while orienting away from negative consequences of that same situation). To address this gap, we performed a series of three fMRI-experiments using simple visual and auditory stimuli in order to (i) determine the neural correlates involved when anticipating a bivalent affective outcome that is both positive and negative at the same time – related to a conflict situation and (ii) investigate their malleability during anticipation via voluntary emotion regulation using attentional focusing. In these studies, we (i) demonstrate that brain areas involved in anticipating positive (ventral striatum) and negative (anterior insula) emotional events are co-activated when anticipating the occurrence of both punishment and reward at the same time and (ii) provide evidence that attention on either the positive or the negative correlates with a shift in activations of these co-activated neural networks and associated anticipated emotions towards either the positive (increased activity in ventral striatum, ventromedial prefrontal cortex, posterior cingulate cortex) or the negative (increased activity in insula) aspect of the upcoming bivalent outcome. In summary, we provide self-report and neural evidence for the assumption that affective brain systems associated with the processing of bivalent anticipated emotions can be voluntarily controlled by cognitive emotion regulation strategies.

YNIMG Journal 2018 Journal Article

Motivational effects on the processing of delayed intentions in the anterior prefrontal cortex

• Jovita Bruening
• Vera U. Ludwig
• Lena M. Paschke
• Henrik Walter
• Christine Stelzel

Delaying intentions bears the risk of interference from distracting activities during the delay interval. Motivation can increase intention retrieval success but little is known about the underlying brain mechanisms. Here, we investigated whether motivational incentives (monetary reward) modulate the processing of delayed intentions in the anterior prefrontal cortex (aPFC), known to be crucial for intention processing. Using a mixed blocked and event-related functional Magnetic Resonance Imaging design, we specifically tested whether reward affects intention processing in the aPFC in a transient or in a sustained manner and whether this is related to individual differences in retrieval success. We found a generalized effect of reward on both correct intention retrieval and ongoing task performance. Fronto-parietal regions including bilateral lateral aPFC showed sustained activity increases in rewarded compared to non-rewarded blocks as well as transient reward-related activity during the storage phase. Additionally, individual differences in reward-related performance benefits were related to the degree of transient signal increases in right lateral aPFC, specifically during intention encoding. This suggests that the ability to integrate motivational relevance into the encoding of future intentions is crucial for successful intention retrieval in addition to general increases in processing effort. Bilateral aPFC is central to these motivation-cognition interactions.

YNIMG Journal 2018 Journal Article

Neural circuitry underlying sustained attention in healthy adolescents and in ADHD symptomatology

• Laura O'Halloran
• Zhipeng Cao
• Kathy Ruddy
• Lee Jollans
• Matthew D. Albaugh
• Andrea Aleni
• Alexandra S. Potter
• Nigel Vahey

Moment-to-moment reaction time variability on tasks of attention, often quantified by intra-individual response variability (IRV), provides a good indication of the degree to which an individual is vulnerable to lapses in sustained attention. Increased IRV is a hallmark of several disorders of attention, including Attention-Deficit/Hyperactivity Disorder (ADHD). Here, task-based fMRI was used to provide the first examination of how average brain activation and functional connectivity patterns in adolescents are related to individual differences in sustained attention as measured by IRV. We computed IRV in a large sample of adolescents (n = 758) across 'Go' trials of a Stop Signal Task (SST). A data-driven, multi-step analysis approach was used to identify networks associated with low IRV (i. e. , good sustained attention) and high IRV (i. e. , poorer sustained attention). Low IRV was associated with greater functional segregation (i. e. , stronger negative connectivity) amongst an array of brain networks, particularly between cerebellum and motor, cerebellum and prefrontal, and occipital and motor networks. In contrast, high IRV was associated with stronger positive connectivity within the motor network bilaterally and between motor and parietal, prefrontal, and limbic networks. Consistent with these observations, a separate sample of adolescents exhibiting elevated ADHD symptoms had increased fMRI activation and stronger positive connectivity within the same motor network denoting poorer sustained attention, compared to a matched asymptomatic control sample. With respect to the functional connectivity signature of low IRV, there were no statistically significant differences in networks denoting good sustained attention between the ADHD symptom group and asymptomatic control group. We propose that sustained attentional processes are facilitated by an array of neural networks working together, and provide an empirical account of how the functional role of the cerebellum extends to cognition in adolescents. This work highlights the involvement of motor cortex in the integrity of sustained attention, and suggests that atypically strong connectivity within motor networks characterizes poor attentional capacity in both typically developing and ADHD symptomatic adolescents.

YNICL Journal 2018 Journal Article

Pedophilic sex offenders are characterised by reduced GABA concentration in dorsal anterior cingulate cortex

• Inka Ristow
• Meng Li
• Lejla Colic
• Vanessa Marr
• Carina Födisch
• Felicia von Düring
• Kolja Schiltz
• Krasimira Drumkova

A pedophilic disorder is characterised by abnormal sexual urges towards prepubescent children. Child abusive behavior is frequently a result of lack of behavioral inhibition and current treatment options entail, next to suppressing unchangeable sexual orientation, measures to increase cognitive and attentional control. We tested, if in brain regions subserving attentional control of behavior and perception of salient stimuli, such inhibition deficit can be observed also on the level of inhibitory neurotransmitters. We measured GABA concentration in the dorsal anterior cingulate cortex (dACC) and in a control region, the pregenual anterior cingulate cortex (pgACC) in pedophilic sex offenders (N = 13) and matched controls (N = 13) using a 7 Tesla STEAM magnetic resonance spectroscopy (MRS). In dACC but not in the control region pedophilic sex offenders showed reduced GABA/Cr concentrations compared to healthy controls. The reduction was robust after controlling for potential influence of age and gray matter proportion within the MRS voxel (p < 0. 04). Importantly, reduced GABA/Cr in patients was correlated with lower self-control measured with the Barratt Impulsiveness Scale (p = 0. 028, r = −0. 689). In a region related to cognitive control and salience mapping, pedophilic sex offenders showed reduction of the inhibitory neurotransmitter GABA which may be seen as a neuronal correlate of inhibition and behavioral control.

YNICL Journal 2018 Journal Article

Processing and regulation of negative emotions in anorexia nervosa: An fMRI study

• Maria Seidel
• Joseph A. King
• Franziska Ritschel
• Ilka Boehm
• Daniel Geisler
• Fabio Bernardoni
• Matthias Beck
• Sophie Pauligk

Theoretical models and recent advances in the treatment of anorexia nervosa (AN) have increasingly focused on the role of alterations in the processing and regulation of emotions. To date, however, our understanding of these changes is still limited and reports of emotional dysregulation in AN have been based largely on self-report data, and there is a relative lack of objective experimental evidence or neurobiological data. The current functional magnetic resonance imaging (fMRI) study investigated the hemodynamic correlates of passive viewing and voluntary downregulation of negative emotions by means of the reappraisal strategy detachment in AN patients. Detachment is regarded as adaptive regulation strategy associated with a reduction in emotion-related amygdala activity and increased recruitment of prefrontal brain regions associated with cognitive control processes. Emotion regulation efficacy was assessed via behavioral arousal ratings and fMRI activation elicited by an established experimental paradigm including negative images. Participants were instructed to either simply view emotional pictures or detach themselves from feelings triggered by the stimuli. The sample consisted of 36 predominantly adolescent female AN patients and a pairwise age-matched healthy control group. Behavioral and neuroimaging data analyses indicated a reduction of arousal and amygdala activity during the regulation condition for both patients and controls. However, compared with controls, individuals with AN showed increased activation in the amygdala as well as in the right dorsolateral prefrontal cortex (dlPFC) during the passive viewing of aversive compared with neutral pictures. These results extend previous findings indicative of altered processing of salient emotional stimuli in AN, but do not point to a general deficit in the voluntary regulation of negative emotions. Increased dlPFC activation in AN during passive viewing of negative stimuli is in line with the hypothesis that the disorder may be characterized by excessive self-control. Taken together, the data seem to suggest that reappraisal via detachment may be an effective strategy to reduce negative arousal for individuals with AN.

YNIMG Journal 2017 Journal Article

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

• Paul M. Thompson
• Ole A. Andreassen
• Alejandro Arias-Vasquez
• Carrie E. Bearden
• Premika S. Boedhoe
• Rachel M. Brouwer
• Randy L. Buckner
• Jan K. Buitelaar

In this review, we discuss recent work by the ENIGMA Consortium (http: //enigma. ini. usc. edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others 1 1 Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative (http: //www. adni-info. org); CHARGE, the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (http: //www. chargeconsortium. com); IMAGEN, IMAging GENetics Consortium (http: //www. imagen-europe. com). , ENIGMA's genomic screens – now numbering over 30, 000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

YNIMG Journal 2017 Journal Article

Evaluating the replicability, specificity, and generalizability of connectome fingerprints

• Lea Waller
• Henrik Walter
• Johann D. Kruschwitz
• Lucia Reuter
• Sabine Müller
• Susanne Erk
• Ilya M. Veer

Establishing reliable, robust, and unique brain signatures from neuroimaging data is a prerequisite for precision psychiatry, and therefore a highly sought-after goal in contemporary neuroscience. Recently, the procedure of connectome fingerprinting, using brain functional connectivity profiles as such signatures, was shown to be able to accurately identify individuals from a group of 126 subjects from the Human Connectome Project (HCP). However, the specificity and generalizability of this procedure were not tested. In this replication study, we show both for the original and an extended HCP data set (n = 900 subjects), as well as for an additional data set of more commonly acquired imaging quality (n = 84) that (i) although the high accuracy can be replicated for the larger HCP 900 data set, accuracy is (ii) lower for standard neuroimaging data, and, that (iii) connectome fingerprinting may not be specific enough to distinguish between individuals. In addition, both accuracy and specificity are projected to drop considerably as the size of a data set increases. Although the moderate-to-high accuracies do suggest there is a portion of unique variance, our results suggest that connectomes may actually be quite similar across individuals. This outcome may be relevant to how precision psychiatry could benefit from inferences based on functional connectomes.

YNIMG Journal 2017 Journal Article

Sliding-window analysis tracks fluctuations in amygdala functional connectivity associated with physiological arousal and vigilance during fear conditioning

• Blazej M. Baczkowski
• Tom Johnstone
• Henrik Walter
• Susanne Erk
• Ilya M. Veer

We evaluated whether sliding-window analysis can reveal functionally relevant brain network dynamics during a well-established fear conditioning paradigm. To this end, we tested if fMRI fluctuations in amygdala functional connectivity (FC) can be related to task-induced changes in physiological arousal and vigilance, as reflected in the skin conductance level (SCL). Thirty-two healthy individuals participated in the study. For the sliding-window analysis we used windows that were shifted by one volume at a time. Amygdala FC was calculated for each of these windows. Simultaneously acquired SCL time series were averaged over time frames that corresponded to the sliding-window FC analysis, which were subsequently regressed against the whole-brain seed-based amygdala sliding-window FC using the GLM. Surrogate time series were generated to test whether connectivity dynamics could have occurred by chance. In addition, results were contrasted against static amygdala FC and sliding-window FC of the primary visual cortex, which was chosen as a control seed, while a physio-physiological interaction (PPI) was performed as cross-validation. During periods of increased SCL, the left amygdala became more strongly coupled with the bilateral insula and anterior cingulate cortex, core areas of the salience network. The sliding-window analysis yielded a connectivity pattern that was unlikely to have occurred by chance, was spatially distinct from static amygdala FC and from sliding-window FC of the primary visual cortex, but was highly comparable to that of the PPI analysis. We conclude that sliding-window analysis can reveal functionally relevant fluctuations in connectivity in the context of an externally cued task.

YNICL Journal 2016 Journal Article

A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder

• Maike C. Herbort
• Joram Soch
• Torsten Wüstenberg
• Kerstin Krauel
• Maia Pujara
• Michael Koenigs
• Jürgen Gallinat
• Henrik Walter

Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI). Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc) to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes.

YNIMG Journal 2016 Journal Article

Neural correlates of training and transfer effects in working memory in older adults

• Stephan Heinzel
• Robert C. Lorenz
• Patricia Pelz
• Andreas Heinz
• Henrik Walter
• Norbert Kathmann
• Michael A. Rapp
• Christine Stelzel

As indicated by previous research, aging is associated with a decline in working memory (WM) functioning, related to alterations in fronto-parietal neural activations. At the same time, previous studies showed that WM training in older adults may improve the performance in the trained task (training effect), and more importantly, also in untrained WM tasks (transfer effects). However, neural correlates of these transfer effects that would improve understanding of its underlying mechanisms, have not been shown in older participants as yet. In this study, we investigated blood-oxygen-level-dependent (BOLD) signal changes during n-back performance and an untrained delayed recognition (Sternberg) task following 12sessions (45min each) of adaptive n-back training in older adults. The Sternberg task used in this study allowed to test for neural training effects independent of specific task affordances of the trained task and to separate maintenance from updating processes. Thirty-two healthy older participants (60–75years) were assigned either to an n-back training or a no-contact control group. Before (t1) and after (t2) training/waiting period, both the n-back task and the Sternberg task were conducted while BOLD signal was measured using functional Magnetic Resonance Imaging (fMRI) in all participants. In addition, neuropsychological tests were performed outside the scanner. WM performance improved with training and behavioral transfer to tests measuring executive functions, processing speed, and fluid intelligence was found. In the training group, BOLD signal in the right lateral middle frontal gyrus/caudal superior frontal sulcus (Brodmann area, BA 6/8) decreased in both the trained n-back and the updating condition of the untrained Sternberg task at t2, compared to the control group. fMRI findings indicate a training-related increase in processing efficiency of WM networks, potentially related to the process of WM updating. Performance gains in untrained tasks suggest that transfer to other cognitive tasks remains possible in aging.

YNIMG Journal 2016 Journal Article

Stimulus-dependent amygdala involvement in affective theory of mind generation

• Mike M. Schmitgen
• Henrik Walter
• Sarah Drost
• Sarah Rückl
• Knut Schnell

Successful social interaction requires knowledge about another person's emotional states, represented in an affective theory of mind (ToM). This information can be acquired either directly or indirectly, i. e. , by observing emotional facial expressions (EFE) or indirectly by inferring emotions through cognitive perspective taking. Therefore, it is of great interest how the function of the cortical ToM network and the limbic system in affective ToM depends on the presence of facial expressions. We addressed this question in a functional magnetic resonance imaging (fMRI) study. The experimental paradigm applied a well-established ToM cartoon task to test functional effects of EFE on the activation of the amygdala and the anterior ToM network during affective ToM judgments. During the task, 22 healthy participants had to judge the changes of the emotional state of the stories protagonist in the presence or absence of EFE. After quality control, 21 data sets entered the final analyses. The presence of EFE during affective ToM judgments was associated with shorter reaction times as well as increased activation of the right amygdala, most probably located in the basolateral nucleus (BLA), coincident with reduced activation of ToM-related regions of the prefrontal cortex. Psychophysiological interactions (PPI) revealed EFE-dependent modulation of connectivity between the right BLA and the contralateral ToM network regions. In combination with the functional interaction of EFE and affective ToM in the right amygdala, our data suggest a complementary but parallel organization of EFE processing and affective ToM. In this framework, the amygdala seems to act as an EFE detector when affective ToM judgments are demanded. Additionally, the facts that EFE induced exclusively right-sided amygdala activation and modulated the connectivity with the contralateral ToM network support the idea of a functional lateralization of stimulus driven components of affective ToM.

YNIMG Journal 2016 Journal Article

Striatal activation as a neural link between cognitive and perceptual flexibility

• Maria Sekutowicz
• Katharina Schmack
• Rosa Steimke
• Lena Paschke
• Philipp Sterzer
• Henrik Walter
• Christine Stelzel

Our brain continuously evaluates different perceptual interpretations of the available sensory data in order to enable flexible updates of conscious experience. Individuals' perceptual flexibility can be assessed using ambiguous stimuli that cause our perception to continuously switch between two mutually exclusive interpretations. Neural processes underlying perceptual switching are thought to involve the visual cortex, but also non-sensory brain circuits that have been implicated in cognitive processes, such as frontal and parietal regions. Perceptual flexibility varies strongly between individuals and has been related to dopaminergic neurotransmission. Likewise, there is also considerable individual variability in tasks that require flexibility in cognition, and dopamine-dependent striato-frontal signals have been associated with processes promoting cognitive flexibility. Given the anatomical and neurochemical similarities with regard to perceptual and cognitive flexibility, we here probed whether individual differences in perceptual flexibility during bistable perception are related to individual cognitive flexibility associated neural correlates. 126 healthy individuals performed rule-based task switching during functional magnetic resonance imaging (fMRI) and reported perceptual switching during the viewing of a modified version of the Necker cube. Mean phase duration as measure of perceptual flexibility correlated with task-switching associated activity in the right putamen as part of the basal ganglia. In addition, we found a tentative correlation between perceptual and cognitive flexibility. These results indicate that individual differences in cognitive flexibility and associated fronto-striatal processing contribute to differences in perceptual flexibility. Our findings thus provide empirical support for the general notion of shared mechanisms between perception and cognition.

YNIMG Journal 2015 Journal Article

Motivation by potential gains and losses affects control processes via different mechanisms in the attentional network

• Lena M. Paschke
• Henrik Walter
• Rosa Steimke
• Vera U. Ludwig
• Robert Gaschler
• Torsten Schubert
• Christine Stelzel

Attentional control in demanding cognitive tasks can be improved by manipulating the motivational state. Motivation to obtain gains and motivation to avoid losses both usually result in faster reaction times and stronger activation in relevant brain areas such as the prefrontal cortex, but little is known about differences in the underlying neurocognitive mechanisms of these types of motivation in an attentional control context. In the present functional magnetic resonance imaging (fMRI) study, we tested whether potential gain and loss as motivating incentives lead to overlapping or distinct neural effects in the attentional network, and whether one of these conditions is more effective than the other. A Flanker task with word stimuli as targets and distracters was performed by 115 healthy participants. Using a mixed blocked and event-related design allowed us to investigate transient and sustained motivation-related effects. Participants could either gain money (potential gain) or avoid losing money (potential loss) in different task blocks. Participants showed a congruency effect with increased reaction times for incongruent compared to congruent trials. Potential gain led to generally faster responses compared to the neutral condition and to stronger improvements than potential loss. Potential loss also led to shorter response times compared to the neutral condition, but participants improved mainly during incongruent and not during congruent trials. The event-related fMRI data revealed a main effect of congruency with increased activity in the left inferior frontal gyrus (IFG) and inferior frontal junction area (IFJ), the pre-supplementary motor area (pre-SMA), bilateral insula, intraparietal sulcus (IPS) and visual word form area (VWFA). While potential gain led to increased activity in a cluster of the IFJ and the VWFA only during incongruent trials, potential loss was linked to activity increases in these regions during incongruent and congruent trials. The block analysis revealed greater activity in gain and loss blocks compared to the neutral condition in most of these regions but no differences in the direct comparison of gain and loss blocks. These findings show that potential monetary gain and loss rely on different mechanisms: Gain was more effective in reducing the reaction time compared to potential loss. Brain data indicate that in the gain context attentional control is executed specifically in incongruent trials, whereas the loss context induces an unspecific increase of attentional control. These findings extend previous studies by providing evidence for diverging neural mechanisms for the effects of different types of motivation on attentional control, specifying the underlying activity patterns in task- and stimulus-related regions.

YNIMG Journal 2014 Journal Article

Common and differential neural networks of emotion regulation by Detachment, Reinterpretation, Distraction, and Expressive Suppression: A comparative fMRI investigation

• Denise Dörfel
• Jan-Peter Lamke
• Falk Hummel
• Ullrich Wagner
• Susanne Erk
• Henrik Walter

Emotions are an indispensable part of our mental life. The term emotion regulation refers to those processes that influence the generation, the experience and the expression of emotions. There is a great variety of strategies to regulate emotions efficiently, which are used in daily life and that have been investigated by cognitive neuroscience. Distraction guides attention to a secondary task. Reinterpretation, a variant of cognitive reappraisal, works by changing the meaning of an emotional stimulus. Detachment, another reappraisal strategy, refers to distancing oneself from an emotional stimulus, thereby reducing its personal relevance. Expressive Suppression modifies the behavioral or physiological response to an emotional stimulus. These four strategies are not equally effective in terms of emotion regulation success and have been shown to partly rely on different neuronal systems. Here, we compare for the first time the neural mechanisms of these typical strategies directly in a common functional magnetic resonance imaging (fMRI) paradigm of downregulation of negative emotions. Our results indicate that three of those strategies (Detachment, Expressive Suppression and Distraction) conjointly increase brain activation in a right prefronto-parietal regulation network and significantly reduce activation of the left amygdala. Compared to the other regulation strategies, Reinterpretation specifically recruited a different control network comprising left ventrolateral prefrontal cortex and orbitofrontal gyrus and was not effective in downregulation of the amygdala. We conclude that Detachment, Distraction and Expressive Suppression recruit very similar emotion regulation networks, whereas Reinterpretation is associated with activation of a qualitatively different network, making this regulation strategy a special one. Notably, Reinterpretation also proved to be the least effective strategy in neural terms, as measured by downregulation of amygdala activation.

YNICL Journal 2014 Journal Article

Larger amygdala volume in first-degree relatives of patients with major depression

• Nina Romanczuk-Seiferth
• Lydia Pöhland
• Sebastian Mohnke
• Maria Garbusow
• Susanne Erk
• Leila Haddad
• Oliver Grimm
• Heike Tost

OBJECTIVE: Although a heritable contribution to risk for major depressive disorder (MDD) has been established and neural alterations in patients have been identified through neuroimaging, it is unclear which brain abnormalities are related to genetic risk. Studies on brain structure of high-risk subjects - such as individuals carrying a familial liability for the development of MDD - can provide information on the potential usefulness of these measures as intermediate phenotypes of MDD. METHODS: 63 healthy first-degree relatives of patients with MDD and 63 healthy controls underwent structural magnetic resonance imaging. Regional gray matter volumes were analyzed via voxel-based morphometry (VBM). RESULTS: Whole-brain analysis revealed significantly larger gray matter volume in the bilateral amygdala in first-degree relatives of patients with MDD. Furthermore, relatives showed significantly larger gray matter volume in anatomical structures found relevant to MDD in previous literature, specifically in the bilateral hippocampus and amygdala as well as the left dorsolateral prefrontal cortex (DLPFC). Bilateral DLPFC volume correlated positively with the experience of negative affect. CONCLUSIONS: Larger gray matter volume in healthy relatives of MDD patients point to a possible vulnerability mechanism in MDD etiology and therefore extend knowledge in the field of high-risk approaches in MDD.

YNIMG Journal 2014 Journal Article

Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects

• Susanne Erk
• Andreas Meyer-Lindenberg
• David E.J. Linden
• Thomas Lancaster
• Sebastian Mohnke
• Oliver Grimm
• Franziska Degenhardt
• Peter Holmans

Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.

YNIMG Journal 2014 Journal Article

Stereoscopic depth increases intersubject correlations of brain networks

• Michael Gaebler
• Felix Biessmann
• Jan-Peter Lamke
• Klaus-Robert Müller
• Henrik Walter
• Stefan Hetzer

Three-dimensional movies presented via stereoscopic displays have become more popular in recent years aiming at a more engaging viewing experience. However, neurocognitive processes associated with the perception of stereoscopic depth in complex and dynamic visual stimuli remain understudied. Here, we investigate the influence of stereoscopic depth on both neurophysiology and subjective experience. Using multivariate statistical learning methods, we compare the brain activity of subjects when freely watching the same movies in 2D and in 3D. Subjective reports indicate that 3D movies are more strongly experienced than 2D movies. On the neural level, we observe significantly higher intersubject correlations of cortical networks when subjects are watching 3D movies relative to the same movies in 2D. We demonstrate that increases in intersubject correlations of brain networks can serve as neurophysiological marker for stereoscopic depth and for the strength of the viewing experience.

YNIMG Journal 2012 Journal Article

Genetic variation in CYP2D6 impacts neural activation during cognitive tasks in humans

• Julia C. Stingl
• Christine Esslinger
• Heike Tost
• Edda Bilek
• Peter Kirsch
• Barbara Ohmle
• Roberto Viviani
• Henrik Walter

The drug metabolizing cytochrome P450 2D6 enzyme (CYP2D6) is highly expressed in brain and potentially involved in neurotransmitter biotransformation. Here, we report the effect of the CYP2D6 genotype on brain activation during a working memory and an emotional face matching task measured with fMRI. Subjects were taken from an ongoing large scale multicenter imaging genetic study. CYP2D6 genotyping of the alleles *2, *3, *4, *5, *6, *9, *10, *17, *35, *41 and the duplication was performed in N =114 healthy drug free individuals. All individuals had completed two tasks in functional brain imaging: an n-back working memory task and an implicit emotional face matching task. Contrast images were analyzed in second-level random effects models with CYP2D6 enzyme activity levels as regressor of interest and age, sex and scanning site as covariates. In the working memory task, a significant effect of CYP2D6 genotype was found in the fusiform gyrus and the precuneus. In the emotional face matching task, an effect was detected in the cuneus. No significant activation results were found in the thalamus. A conjunction analysis confirmed a significant joint effect of the CYP2D6 association in both regions. In both tasks activation increased with increasing CYP2D6 activity. In conclusion, we confirmed a central nervous system effect of CYP2D6 activity in a large independent sample using a different imaging modality, and provide evidence that basic cognitive processes related to such as alertness may be impacted.

YNIMG Journal 2012 Journal Article

Test–retest reliability of resting-state connectivity network characteristics using fMRI and graph theoretical measures

• Urs Braun
• Michael M. Plichta
• Christine Esslinger
• Carina Sauer
• Leila Haddad
• Oliver Grimm
• Daniela Mier
• Sebastian Mohnke

Characterizing the brain connectome using neuroimaging data and measures derived from graph theory emerged as a new approach that has been applied to brain maturation, cognitive function and neuropsychiatric disorders. For a broad application of this method especially for clinical populations and longitudinal studies, the reliability of this approach and its robustness to confounding factors need to be explored. Here we investigated test–retest reliability of graph metrics of functional networks derived from functional magnetic resonance imaging (fMRI) recorded in 33 healthy subjects during rest. We constructed undirected networks based on the Anatomic-Automatic-Labeling (AAL) atlas template and calculated several commonly used measures from the field of graph theory, focusing on the influence of different strategies for confound correction. For each subject, method and session we computed the following graph metrics: clustering coefficient, characteristic path length, local and global efficiency, assortativity, modularity, hierarchy and the small-worldness scalar. Reliability of each graph metric was assessed using the intraclass correlation coefficient (ICC). Overall ICCs ranged from low to high (0 to 0. 763) depending on the method and metric. Methodologically, the use of a broader frequency band (0. 008–0. 15Hz) yielded highest reliability indices (mean ICC=0. 484), followed by the use of global regression (mean ICC=0. 399). In general, the second order metrics (small-worldness, hierarchy, assortativity) studied here, tended to be more robust than first order metrics. In conclusion, our study provides methodological recommendations which allow the computation of sufficiently robust markers of network organization using graph metrics derived from fMRI data at rest.

YNIMG Journal 2011 Journal Article

Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A

• Christine Esslinger
• Peter Kirsch
• Leila Haddad
• Daniela Mier
• Carina Sauer
• Susanne Erk
• Knut Schnell
• Claudia Arnold

Alterations of connectivity are central to the systems-level pathophysiology of schizophrenia. One of the best-established genome-wide significant risk variants for this highly heritable disorder, the rs1344706 single nucleotide polymorphism in ZNF804A, was recently shown to modulate connectivity in healthy carriers during working memory (WM) in a pattern mirroring that which was found in overt disease. However, it was unclear whether this finding is specific to WM or if it is present regardless of cognitive state. Therefore, we examined genotype effects on connectivity in healthy carriers during rest and an emotion processing task without WM component. 111 healthy German subjects performed a battery of functional imaging tasks. Functional connectivity with the right dorsolateral prefrontal cortex during rest and an implicit emotion recognition task was determined using the seed voxel method and compared to results during WM. During rest and during the emotional task, a pattern of reduced interhemispheric prefrontal connectivity with increasing number of rs1344706 risk alleles could be seen that was close to identical to that during WM, suggesting a state-independent influence of the genetic variant on interhemispheric processing, possibly through structural effects. By contrast, the abnormal prefronto-hippocampal connectivity was only seen during the WM task, indicating a degree of task specificity in agreement with prior results in patients with schizophrenia. Our findings confirm a key role for disturbed functional connectivity in the genetic risk architecture of schizophrenia and identify cognitive state-dependent and independent components with regard to WM function.

YNIMG Journal 2011 Journal Article

Functional relations of empathy and mentalizing: An fMRI study on the neural basis of cognitive empathy

• Knut Schnell
• Sarah Bluschke
• Brigitte Konradt
• Henrik Walter

This fMRI study was set up to explore how cognitive empathy, i. e. the cognitive inference on another person's affective state, can be characterized as a distinct brain function relating to pre-existing neurofunctional concepts about mentalizing and empathy. In a 3 Tesla MRI scanner 28 healthy participants were presented with four different instructions randomly combined with 32 false-belief cartoon stories of 3 subsequent pictures free of direct cues for affective states, like e. g. facial expressions. Participants were instructed to judge affective or visuospatial changes from their own (1st person perspective) or the protagonists' (3rd person perspective, 3rdpp) perspective. 3rdpp-judgements about affective states differed from visuospatial 3rdpp judgements by a significantly higher activation of the anterior mentalizing network (dorsomedial prefrontal cortex, anterior superior temporal sulcus, temporal poles) and the limbic system (left amygdala and hippocampus). Analysis of main effects revealed that the anterior part of the mentalizing network was activated significantly stronger by affective compared to visuospatial content. In contrast, the temporoparietal junction was rather activated by 3rdpp visuospatial judgements. After all, our results demonstrate a functional dissociation between cognitive empathy and cognitive visuospatial perspective taking. The simultaneous activation of the cortical mentalizing network and the amygdala indicates that cognitive empathy actually involves reference to own affective states in the observer. Notably, the cognitive reference to own affective states activated the mentalizing network as well. Moreover our results support pre-existing ideas about a functional anterior–posterior subdivision of the mentalizing network, depending on affective content and 3rd person perspective of cognition.

YNIMG Journal 2010 Journal Article

Volition diminishes genetically mediated amygdala hyperreactivity

• Dina M. Schardt
• Susanne Erk
• Corinna Nüsser
• Markus M. Nöthen
• Sven Cichon
• Marcella Rietschel
• Jens Treutlein
• Thomas Goschke

Individuals carrying the short allele of a common polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) exhibit heightened amygdala responses to passive stimulation with aversive emotional material. In turn, the level of amygdala activation in response to emotion can be decreased by will, for example by using cognitive emotion regulation strategies. In the present study, 37 female subjects (s-carriers: n =21; l/l-homozygotes: n =16) performed an emotion regulation task during functional magnetic resonance imaging to determine whether cognitive emotion regulation can modulate the genetically determined amygdala hyperreactivity in 5-HTTLPR short allele carriers. Our results demonstrate that cognitive emotion regulation diminishes the difference in amygdala reactivity to threat-related stimuli between 5-HTTLPR genotype groups. Furthermore, we also provide evidence that the effect of cognitive regulation is mediated through altered coupling between the amygdala and prefrontal regulatory regions. Our findings demonstrate that while the presence of the 5-HTTLPR short allele leads to heightened responses in the amygdala, cognitive regulation can modify genetically mediated effects upon brain function by volitionally altering prefrontal-amygdala connectivity.

YNIMG Journal 2009 Journal Article

Cognitive reappraisal modulates expected value and prediction error encoding in the ventral striatum

• Markus R. Staudinger
• Susanne Erk
• Birgit Abler
• Henrik Walter

In addiction, loss of prefrontal inhibitory control is believed to contribute to impulsivity. To improve cognitive therapy approaches, it is important to determine whether cognitive control strategies can generally influence reward processing at the neural level. We investigated the effects of one such strategy—namely, reappraisal (distancing from feelings)—on neural reward processing in 16 healthy subjects by utilizing event-related functional magnetic resonance imaging (fMRI). In a monetary incentive delay task, expected reward value (expecting to win €0. 50 vs. €0. 10) and outcome valence (win vs. omission) were varied. An attenuation of expected value and a modulation of prediction error (PE) coding caused by distancing were found in right vs. left ventral striatum (VST) in the expectation vs. outcome period, respectively. Distancing from reward feelings recruited a right hemispheric fronto-parietal network. Moreover, self-reported reappraisal success (decrease of feelings by distancing) showed a trend toward positive correlation with activation in the rostral cingulate zone and the lateral orbitofrontal cortex, both part of the regulation network. Our results expand upon recent findings by showing that cognitive control over reward processing impacts not only the expectation period but also the reward signals in the outcome period. Moreover, increased recruitment of prefrontal reflective subsystems might enhance deliberate control over both reward processing and hedonic experience.

YNIMG Journal 2007 Journal Article

Valence-specific regulation effects in a working memory task with emotional context

• Susanne Erk
• Anna Kleczar
• Henrik Walter

The modulatory effects of emotional context on episodic memory have been shown recently. We were interested whether working memory is similarly susceptible to emotional context or whether working memory helps to distract from emotion, i. e. serves to downregulate emotional reactions in order to sustain the prior intention. We tested the effects of emotional stimulation during active maintenance of information by modulating the emotional context of maintenance processes in a Sternberg item recognition task with two load conditions. Behavioral data revealed no impairment of working memory performance during emotional context. Actually, behavioral performance was better for emotional compared to neutral context during high load. Furthermore, emotional context had no interference effect on working memory-related brain activation. Instead, we found a valence-specific regulation effect: High cognitive effort was associated with reduced activity in emotion processing regions, i. e. the amygdala and ventral striatum. This effect was mediated by different prefrontal regions, i. e. by left inferior PFC for negative and left superior PFC for positive valence. Furthermore, our results reveal an integration effect of emotion and cognition in right dorsolateral prefrontal cortex showing increased recruitment with increasing complexity of the task. The results presented here are of relevance for the understanding of regulatory mechanisms and diseases characterized by increased susceptibility to emotional distraction.

YNIMG Journal 2007 Journal Article

Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: Evidence from event-related fMRI

• Henrik Walter
• Nenad Vasic
• Annett Höse
• Manfred Spitzer
• Robert Christian Wolf

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including the lateral prefrontal cortex, superior temporal areas and the striatum. However, less is known about the relationship of WM-dysfunction, cerebral activation, task-accuracy and diagnostic specificity. Using a novel WM-task and event-related functional magnetic resonance imaging (fMRI), we studied healthy control subjects (n =17) and partially remitted, medicated inpatients meeting DSM-IV criteria for schizophrenia (n =19) and major depressive disorder (n =12). Due to the event-related technique, we excluded incorrectly performed trials, thus controlling for accuracy-related activation confounds. Compared with controls, patients with schizophrenia showed less activation in frontoparietal and subcortical regions at high cognitive load levels. Compared with patients with depression, schizophrenic patients showed less prefrontal activation in left inferior frontal cortex and right cerebellum. In patients with schizophrenia, a lack of deactivation of the superior temporal cortex was found compared to both healthy controls and patients with depression. Thus, we could not confirm previous findings of impaired lateral prefrontal activation during WM performance in schizophrenic patients after the exclusion of incorrectly performed or omitted trials in our functional analysis. However, superior temporal cortex dysfunction in patients with schizophrenia may be regarded as schizophrenia-specific finding in terms of psychiatric diagnosis specificity.

YNIMG Journal 2006 Journal Article

Prediction error as a linear function of reward probability is coded in human nucleus accumbens

• Birgit Abler
• Henrik Walter
• Susanne Erk
• Hannes Kammerer
• Manfred Spitzer

Reward probability has been shown to be coded by dopamine neurons in monkeys. Phasic neuronal activation not only increased linearly with reward probability upon expectation of reward, but also varied monotonically across the range of probabilities upon omission or receipt of rewards, therefore modeling discrepancies between expected and received rewards. Such a discrete coding of prediction error has been suggested to be one of the basic principles of learning. We used functional magnetic resonance imaging (fMRI) to show that the human dopamine system codes reward probability and prediction error in a similar way. We used a simple delayed incentive task with a discrete range of reward probabilities from 0%–100%. Activity in the nucleus accumbens of human subjects strongly resembled the phasic responses found in monkey neurons. First, during the expectation period of the task, the fMRI signal in the human nucleus accumbens (NAc) increased linearly with the probability of the reward. Second, during the outcome phase, activity in the NAc coded the prediction error as a linear function of reward probabilities. Third, we found that the Nac signal was correlated with individual differences in sensation seeking and novelty seeking, indicating a link between individual fMRI activation of the dopamine system in a probabilistic paradigm and personality traits previously suggested to be linked with reward processing. We therefore identify two different covariates that model activity in the Nac: specific properties of a psychological task and individual character traits.

YNIMG Journal 2005 Journal Article

Emotional context during encoding of neutral items modulates brain activation not only during encoding but also during recognition

• Susanne Erk
• Sonja Martin
• Henrik Walter

In general, encoding of neutral material includes the context in which the respective material is learned. The effect of emotional context on successfully encoded neutral material has been investigated only recently in few studies, but the main underlying mechanisms are still fairly unknown. In the present study, we investigated the effect of positive and negative emotional context on encoding and later recognition of neutral items. We could demonstrate that brain activation not only during encoding but also during recognition of neutral items depended on the emotional valence of the encoding context. Whereas activation of medial temporal lobe structures during encoding specifically predicted subsequent memory when learning appears in a positive emotional context, activation of the anterior temporal cortex in a region with afferent input to the amygdala predicted memory for material learned in negative context. Recognition of items encoded in positive emotional context revealed activation of hippocampal and medial prefrontal regions, recognition of items encoded in negative emotional context revealed activation of the caudate nucleus. We assume that our findings reflect the recruitment of different brain circuits depending on the emotional context during learning.

YNIMG Journal 2003 Journal Article

Emotional context modulates subsequent memory effect

• Susanne Erk
• Markus Kiefer
• J.o Grothe
• Arthur P Wunderlich
• Manfred Spitzer
• Henrik Walter

Emotions have been shown to modulate memory processes. However, the neuronal substrate underlying these modulatory effects is largely unknown. Using event-related functional magnetic resonance imaging (fMRI), we investigated whether the context of emotional encoding modulates brain activation predictive for subsequent recall of emotionally neutral material. While inferior frontal activation predicted recall in general, our data show that in a positive encoding context, recall was predicted by activation of right anterior parahippocampal and extrastriate visual brain areas, whereas in a negative encoding context, recall was predicted by activation of the amygdala. Thus, we could demonstrate that successful episodic encoding is differentially modulated by emotional context. These results contribute to the understanding of the interaction of emotion and cognition and moreover are of general relevance for studies of episodic memory.

YNIMG Journal 2002 Journal Article

Dissociating a Common Working Memory Network from Different Neural Substrates of Phonological and Spatial Stimulus Processing

• Bartosz Zurowski
• Julia Gostomzyk
• Georg Grön
• Rolf Weller
• Holger Schirrmeister
• Bernd Neumeier
• Manfred Spitzer
• Sven N. Reske

Positron emission tomography was used to investigate common versus specific cortical regions for the maintenance of spatial versus phonological information in working memory (WM). Group and single-subject analyses of regional cerebral blood flow during a new 2 × 2 factorial n-back task were performed. Eight subjects had to memorize either phonological features or the location of serially presented syllables. Brain activation during phonological judgment and spatial judgment (0-back) was compared with that during two corresponding WM conditions (2-back). We observed a common network associated with the requirement of maintaining and sequencing items in WM. Seven or more subjects activated (posterior) superior frontal sulcus (pSFS, BA 6/8, global maximum) and/or adjacent gyri, posterior parietal cortex, and precuneus (BA 7). Less consistently, bilateral middle frontal gyrus (BA 9/46) was involved. Bilateral anterior (BA 39/40) and posterior (BA 7) intraparietal sulcus, as well as right pSFS, exhibited dominance for spatial WM. Although underlying stimulus processing pathways for both types of information were different, no region specific for phonological WM was found. Robust activation within the left inferior frontal gyrus (BA 44 and 45) was present, during both phonological WM and phonological judgment. We conclude that the controversial left prefrontal lateralization for verbal WM reflects more general phonological processing strategies, not necessarily required by tasks using letters. We propose a stimulus-independent role for the bilateral pSFS and its vicinity for maintenance and manipulation of different context-dependent information within working memory.

YNIMG Journal 2001 Journal Article

Detection of delay selective activity during a working memory task by explorative data analysis

• Andrzej Wichert
• Henrik Walter
• Georg Groen
• Axel Baune
• Jo Grothe
• Arthur Wunderlich
• Friedrich T. Sommer

YNIMG Journal 2001 Journal Article

Modulation of episodic memory encoding by emotional stimulation in fMRI

• Susanne Erk
• Markus Kiefer
• Jo Grothe
• Arthur P. Wunderlich
• Manfred Spitzer
• Henrik Walter

YNIMG Journal 2001 Journal Article

Phonological and visuospatial working memory: A common network and sources of lateralization

• Bartosz Zurowski
• Julia Gostomzyk
• Georg Groen
• Rolf Weller
• Holger Schirrmeister
• Bernd Neumeier
• Manfred Spitzer
• Sven N. Reske

YNIMG Journal 2001 Journal Article

The neural correlates of driving and co-driving

• Henrik Walter
• Sandra Vetter
• Jo Grothe
• Arthur P. Wunderlich
• Stefan Hahn
• Manfred Spitzer

YNIMG Journal 2000 Journal Article

Altered neural activation patterns in schizophrenic patients during a verbal and a visuospatial working memory task: and fMRI study

• Henrik Walter
• Michael Blankenhorn
• Georg Groen
• Sandra Schaefer
• Arthur Wunderlich
• Reinhard Tomczak
• Manfred Spitzer

YNIMG Journal 2000 Journal Article

Performance dependent brain activity during recall of abstract visual patterns

• Georg Groen
• Daniel Bittner
• Bernd Schmitz
• Arthur Wunderlich
• Reinhard Tomczak
• Henrik Walter
• Matthias Riepe