Predictors of adherence to exercise interventions in people with schizophrenia.

Exercise interventions are nowadays considered as effective add-on treatments in people with schizophrenia but are usually associated with high dropout rates. Therefore, the present study investigated potential predictors of adherence from a large multicenter study, encompassing two types of exercise training, conducted over a 6-month period with individuals with schizophrenia. First, we examined the role of multiple participants' characteristics, including levels of functioning, symptom severity, cognitive performance, quality of life, and physical fitness. Second, we used K-means clustering to identify clinical subgroups of participants that potentially exhibited superior adherence. Last, we explored if adherence could be predicted on the individual level using Random Forest, Logistic Regression, and Ridge Regression. We found that individuals with higher levels of functioning at baseline were more likely to adhere to the exercise interventions, while other factors such as symptom severity, cognitive performance, quality of life or physical fitness seemed to be less influential. Accordingly, the high-functioning group with low symptoms exhibited a greater likelihood of adhering to the interventions compared to the severely ill group. Despite incorporating various algorithms, it was not possible to predict adherence at the individual level. These findings add to the understanding of the factors that influence adherence to exercise interventions. They underscore the predictive importance of daily life functioning while indicating a lack of association between symptom severity and adherence. Future research should focus on developing targeted strategies to improve adherence, particularly for people with schizophrenia who suffer from impairments in daily functioning.Clinical trials registration The study of this manuscript which the manuscript is based was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1 ) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804.

Aerobic endurance training to improve cognition and enhance recovery in schizophrenia: design and methodology of a multicenter randomized controlled trial.

Even today, patients with schizophrenia often have an unfavorable outcome. Negative symptoms and cognitive deficits are common features in many patients and prevent recovery. In recent years, aerobic endurance training has emerged as a therapeutic approach with positive effects on several domains of patients' health. However, appropriately sized, multicenter randomized controlled trials that would allow better generalization of results are lacking. The exercise study presented here is a multicenter, rater-blind, two-armed, parallel-group randomized clinical trial in patients with clinically stable schizophrenia being conducted at five German tertiary hospitals. The intervention group performs aerobic endurance training on bicycle ergometers three times per week for 40-50 min/session (depending on the intervention week) for a total of 26 weeks, and the control group performs balance and tone training for the same amount of time. Participants are subsequently followed up for 26 weeks. The primary endpoint is all-cause discontinuation; secondary endpoints include psychopathology, cognition, daily functioning, cardiovascular risk factors, and explorative biological measures regarding the underlying mechanisms of exercise. A total of 180 patients will be randomized. With currently 162 randomized participants, our study is the largest trial to date to investigate endurance training in patients with schizophrenia. We hypothesize that aerobic endurance training has beneficial effects on patients' mental and physical health, leading to lower treatment discontinuation rates and improving disease outcomes. The study results will provide a basis for recommending exercise interventions as an add-on therapy in patients with schizophrenia.The study is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence.

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.

Amygdala functional connectivity in major depression - disentangling markers of pathology, risk and resilience.

BACKGROUND: Limbic-cortical imbalance is an established model for the neurobiology of major depressive disorder (MDD), but imaging genetics studies have been contradicting regarding potential risk and resilience mechanisms. Here, we re-assessed previously reported limbic-cortical alterations between MDD relatives and controls in combination with a newly acquired sample of MDD patients and controls, to disentangle pathology, risk, and resilience. METHODS: We analyzed functional magnetic resonance imaging data and negative affectivity (NA) of MDD patients (n = 48), unaffected first-degree relatives of MDD patients (n = 49) and controls (n = 109) who performed a faces matching task. Brain response and task-dependent amygdala functional connectivity (FC) were compared between groups and assessed for associations with NA. RESULTS: Groups did not differ in task-related brain activation but activation in the superior frontal gyrus (SFG) was inversely correlated with NA in patients and controls. Pathology was associated with task-independent decreases of amygdala FC with regions of the default mode network (DMN) and decreased amygdala FC with the medial frontal gyrus during faces matching, potentially reflecting a task-independent DMN predominance and a limbic-cortical disintegration during faces processing in MDD. Risk was associated with task-independent decreases of amygdala-FC with fronto-parietal regions and reduced faces-associated amygdala-fusiform gyrus FC. Resilience corresponded to task-independent increases in amygdala FC with the perigenual anterior cingulate cortex (pgACC) and increased FC between amygdala, pgACC, and SFG during faces matching. CONCLUSION: Our results encourage a refinement of the limbic-cortical imbalance model of depression. The validity of proposed risk and resilience markers needs to be tested in prospective studies. Further limitations are discussed.

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.

Evidence for superior neurobiological and behavioral inhibitory control abilities in non-offending as compared to offending pedophiles.

Neurobehavioral models of pedophilia and child sexual offending suggest a pattern of temporal and in particular prefrontal disturbances leading to inappropriate behavioral control and subsequently an increased propensity to sexually offend against children. However, clear empirical evidence for such mechanisms is still missing. Using a go/nogo paradigm in combination with functional magnetic resonance imaging (fMRI) we compared behavioral performance and neural response patterns among three groups of men matched for age and IQ: pedophiles with (N = 40) and without (N = 37) a history of hands-on sexual offences against children as well as healthy non-offending controls (N = 40). As compared to offending pedophiles, non-offending pedophiles exhibited superior inhibitory control as reflected by significantly lower rate of commission errors. Group-by-condition interaction analysis also revealed inhibition-related activation in the left posterior cingulate and the left superior frontal cortex that distinguished between offending and non-offending pedophiles, while no significant differences were found between pedophiles and healthy controls. Both areas showing distinct activation pattern among pedophiles play a critical role in linking neural networks that relate to effective cognitive functioning. Data therefore suggest that heightened inhibition-related recruitment of these areas as well as decreased amount of commission errors is related to better inhibitory control in pedophiles who successfully avoid committing hands-on sexual offences against children. Hum Brain Mapp 38:1092-1104, 2017. © 2016 Wiley Periodicals, Inc.

Executive Functioning in Pedophilia and Child Sexual Offending.

OBJECTIVES: Pedophilia (P) is a psychiatric disease associated with sexual attraction toward children and often accompanied by child sexual offending (CSO). Consequently, it is important to address the understanding of executive dysfunctions that may increase the probability of CSO. Moreover, this research field has been lacking to disentangle executive deficits associated with pedophilia (as a deviant sexual preference) from those associated with CSO (as a deviant sexual behavior). METHODS: The German multi-sided research network NeMUP offers the opportunity to overcome these limitations. By applying the Cambridge Automated Neuropsychological Test Battery in four carefully matched groups of men: (1) pedophiles with (N=45) and (2) without (N=45) a history of sexual offending against children; (3) child molesters without pedophilia (N=19), and (4) non-offending controls (N=49), we were able to analyze executive functioning in pedophilia and CSO independently. RESULTS: Both CSO groups as compared to both non-CSO groups exhibited worsened response inhibition ability. However, only non-pedophilic offenders showed additionally disabled strategy use ability. Regarding set-shifting abilities, the P+CSO group showed the best performance. We also found that performances were affected by age: only in pedophiles, response inhibition worsened with age, while age-related deficits in set-shifting abilities were restricted to non-pedophilic participants. The latter also differentiated between both sexual preference groups. CONCLUSIONS: Our results are the first to demonstrate that executive dysfunctions are related to offense status rather than pedophilic preference. Furthermore, there was evidence for differentiating age and performance correlations between pedophiles and non-pedophiles, which warrants further investigation. (JINS, 2017, 23, 460-470).

Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain.

Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity.

Segregation of face sensitive areas within the fusiform gyrus using global signal regression? A study on amygdala resting-state functional connectivity.

The application of global signal regression (GSR) to resting-state functional magnetic resonance imaging data and its usefulness is a widely discussed topic. In this article, we report an observation of segregated distribution of amygdala resting-state functional connectivity (rs-FC) within the fusiform gyrus (FFG) as an effect of GSR in a multi-center-sample of 276 healthy subjects. Specifically, we observed that amygdala rs-FC was distributed within the FFG as distinct anterior versus posterior clusters delineated by positive versus negative rs-FC polarity when GSR was performed. To characterize this effect in more detail, post hoc analyses revealed the following: first, direct overlays of task-functional magnetic resonance imaging derived face sensitive areas and clusters of positive versus negative amygdala rs-FC showed that the positive amygdala rs-FC cluster corresponded best with the fusiform face area, whereas the occipital face area corresponded to the negative amygdala rs-FC cluster. Second, as expected from a hierarchical face perception model, these amygdala rs-FC defined clusters showed differential rs-FC with other regions of the visual stream. Third, dynamic connectivity analyses revealed that these amygdala rs-FC defined clusters also differed in their rs-FC variance across time to the amygdala. Furthermore, subsample analyses of three independent research sites confirmed reliability of the effect of GSR, as revealed by similar patterns of distinct amygdala rs-FC polarity within the FFG. In this article, we discuss the potential of GSR to segregate face sensitive areas within the FFG and furthermore discuss how our results may relate to the functional organization of the face-perception circuit.

Alterations in neural Theory of Mind processing in euthymic patients with bipolar disorder and unaffected relatives.

OBJECTIVES: Behavioral deficits in the Theory of Mind (ToM) have been robustly demonstrated in bipolar disorder. These deficits may represent an intermediate phenotype of the disease. The aim of this study was: (i) to investigate alterations in neural ToM processing in euthymic patients with bipolar disorder, and (ii) to examine whether similar effects are present in unaffected relatives of patients with bipolar disorder suggesting that ToM functional activation may be, in part, due to genetic risk for the disease. METHODS: A total of 24 euthymic patients with bipolar disorder, 21 unaffected first-degree relatives, and 81 healthy controls completed a ToM task while undergoing functional magnetic resonance imaging. RESULTS: We observed reduced bilateral activation of the temporoparietal junction (TPJ) and diminished functional fronto-temporoparietal connectivity in patients compared to controls. Relatives tended towards intermediate temporoparietal activity and functional coupling with medial prefrontal areas. There was also evidence for a potentially compensatory enhanced recruitment of the right middle temporal gyrus and stronger connectivity between this region and the medial prefrontal cortex in relatives. CONCLUSIONS: These findings provide further evidence of altered neural ToM processing in euthymic patients with bipolar disorder. Further, our findings in relatives lend support to the idea that altered ToM processing may act as an intermediate phenotype of the disorder.

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

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.

The architecture of paranoia in the general population: A self-report and ecological momentary assessment study.

Paranoia is a common delusion type found in clinical and non-clinical populations. A hierarchical, dimensional model of paranoia in the general population has been proposed, with four categories representing increasing levels of paranoia: interpersonal sensitivity (IP), mistrust (M), ideas of reference (IR), persecutory ideas (PI). What is currently lacking and could provide insights into etiology is a comprehensive clinical characterization of the lower end of the paranoia spectrum, psychological domains that are associated with symptom severity, and how paranoia and its structure fluctuate over time. This study conducted both cross-sectional and longitudinal surveys with 802 participants from the German population assessing paranoia and general psychopathology. Data was collected through Ecological Momentary Assessment (EMA). Several statistical approaches were used including confirmatory factor analysis (CFA), latent class analysis (LCA) and mixed modelling analyses (ME). Paranoid experiences appear to be a common phenomenon that occur in people with and without mental illness. Subjects clustered into four paranoia severity subgroups (IP, M, IR, PI) and showed significant associations in various psychological domains like increased psychiatric symptoms and maladaptive coping. Paranoia fluctuates over time in all four severity subgroups, but the hierarchical subgrouping was stable. Both persecutory ideations and interpersonal sensitivity were significant predictors of paranoia. Findings provide important insights into the architecture of paranoia in the German population by characterizing their hierarchical, dimensional, and dynamic structure and its link to psychopathology.

Effects of Exercise on Structural and Functional Brain Patterns in Schizophrenia-Data From a Multicenter Randomized-Controlled Study.

BACKGROUND AND HYPOTHESIS: Aerobic exercise interventions in people with schizophrenia have been demonstrated to improve clinical outcomes, but findings regarding the underlying neural mechanisms are limited and mainly focus on the hippocampal formation. Therefore, we conducted a global exploratory analysis of structural and functional neural adaptations after exercise and explored their clinical implications. STUDY DESIGN: In this randomized controlled trial, structural and functional MRI data were available for 91 patients with schizophrenia who performed either aerobic exercise on a bicycle ergometer or underwent a flexibility, strengthening, and balance training as control group. We analyzed clinical and neuroimaging data before and after 6 months of regular exercise. Bayesian linear mixed models and Bayesian logistic regressions were calculated to evaluate effects of exercise on multiple neural outcomes and their potential clinical relevance. STUDY RESULTS: Our results indicated that aerobic exercise in people with schizophrenia led to structural and functional adaptations mainly within the default-mode network, the cortico-striato-pallido-thalamo-cortical loop, and the cerebello-thalamo-cortical pathway. We further observed that volume increases in the right posterior cingulate gyrus as a central node of the default-mode network were linked to improvements in disorder severity. CONCLUSIONS: These exploratory findings suggest a positive impact of aerobic exercise on 3 cerebral networks that are involved in the pathophysiology of schizophrenia. CLINICAL TRIALS REGISTRATION: The underlying study of this manuscript was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Investigating the neural correlates of affective mentalizing and their association with general intelligence in patients with schizophrenia.

BACKGROUND AND HYPOTHESIS: Mentalizing impairment in schizophrenia has been linked to altered neural responses. This study aimed to replicate previous findings of altered activation of the mentalizing network in schizophrenia and investigate its possible association with impaired domain-general cognition. STUDY DESIGN: We analyzed imaging data from two large multi-centric German studies including 64 patients, 64 matched controls and a separate cohort of 300 healthy subjects, as well as an independent Australian study including 46 patients and 61 controls. All subjects underwent functional magnetic resonance imaging while performing the same affective mentalizing task and completed a cognitive assessment battery. Group differences in activation of the mentalizing network were assessed by classical as well as Bayesian two-sample t-tests. Multiple regression analysis was performed to investigate effects of neurocognitive measures on activation of the mentalizing network. STUDY RESULTS: We found no significant group differences in activation of the mentalizing network. Bayes factors indicate that these results provide genuine evidence for the null hypothesis. We found a positive association between verbal intelligence and activation of the medial prefrontal cortex, a key region of the mentalizing network, in three independent samples. Finally, individuals with low verbal intelligence showed altered activation in areas previously implicated in mentalizing dysfunction in schizophrenia. CONCLUSIONS: Mentalizing activation in patients with schizophrenia might not differ compared to large well-matched groups of healthy controls. Verbal intelligence is an important confounding variable in group comparisons, which should be considered in future studies of the neural correlates of mentalizing dysfunction in schizophrenia.

Exercise as an add-on treatment in individuals with schizophrenia: Results from a large multicenter randomized controlled trial.

Current treatment methods do not achieve recovery for most individuals with schizophrenia, and symptoms such as negative symptoms and cognitive deficits often persist. Aerobic endurance training has been suggested as a potential add-on treatment targeting both physical and mental health. We performed a large-scale multicenter, rater-blind, parallel-group randomized controlled clinical trial in individuals with stable schizophrenia. Participants underwent a professionally supervised six-month training comprising either aerobic endurance training (AET) or flexibility, strengthening, and balance training (FSBT, control group), follow-up was another six months. The primary endpoint was all-cause discontinuation (ACD); secondary endpoints included effects on psychopathology, cognition, functioning, and cardiovascular risk. In total, 180 participants were randomized. AET was not superior to FSBT in ACD and most secondary outcomes, with dropout rates of 59.55% and 57.14% in the six-month active phase, respectively. However, both groups showed significant improvements in positive, general, and total symptoms, levels of functioning and in cognitive performance. A higher training frequency additionally promoted further memory domains. Participants with higher baseline cognitive abilities were more likely to respond to the interventions. Our results support integrating exercise into schizophrenia treatment, while future studies should aim to develop personalized training recommendations to maximize exercise-induced benefits.

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

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 (0.008-0.15 Hz) 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.

Neural processing associated with cognitive empathy in pedophilia and child sexual offending.

Behavioral studies found evidence for superior cognitive empathy (CE) in pedophilic men without a history of child sexual offending (P - CSO) compared to pedophilic men with a history of child sexual offending (P + CSO). Functional magnetic resonance imaging (fMRI) studies also point to differences between P - CSO and P + CSO. Neural processing associated with CE has not yet been investigated. Therefore, the present study aimed to explore the neural correlates of CE in subjects with pedophilia with (P + CSO) and without (P - CSO) child sexual offending. 15 P + CSO, 15 P - CSO and 24 teleiophilic male controls (TC) performed a CE task during fMRI. We observed reduced activation in the left precuneus (Pcu) and increased activation in the left anterior cingulate cortex (ACC) in P - CSO compared to P + CSO. P - CSO also showed stronger connectivity between these regions, which might reflect a top-down modulation of the Pcu by the ACC toward an increased self-focused emotional reaction in social situations. There was also evidence for increased right superior temporal gyrus activation in P - CSO that might constitute a potentially compensatory recruitment due to the dampened Pcu activation. These findings provide first evidence for altered neural processing of CE in P - CSO and underline the importance of addressing CE in pedophilia and CSO in order to uncover processes relevant to effective prevention of child sexual abuse.