While several recent imaging studies confirm that motor foot areas can still be activated in complete and chronic paraplegia, it remains unclear whether their functionality is also maintained or declines after years of "non-use". Force control is one of the most important and best investigated functions within the motor cortex. It has been repeatedly reported that the motor cortex is more active when higher forces have to be applied. We thus addressed the question of preserved cortical functions by comparing motor force control patterns in the event-related potentials of 10 motor complete paraplegic subjects and 10 controls after attempted (paraplegic patients)/executed (healthy controls) ballistic foot movements with three different force levels. In addition to the peak amplitudes reflecting force levels, peak latencies were also investigated to elucidate timing as another functional aspect of motor control. No significant group difference was found for the peak latencies, indicating that the timing of motor cortical activation is preserved. Concerning amplitudes, we found preserved cortical modulation of higher forces but distorted low force modulation, especially early after injury. These findings thus suggest that important aspects of cortical control over paralyzed limbs are maintained despite years of "non-use".

Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.

Children who are poor readers usually experience troublesome school careers and consequently often suffer from secondary emotional and behavioural problems. Early identification and prediction of later reading problems thus are critical in order to start targeted interventions for those children with an elevated risk for emerging reading problems. In this study, behavioural precursors of reading were assessed in nineteen (aged 6.4 ± 0.3 years) non-reading kindergarteners before training letter-speech sound associations with a computerized game (Graphogame) for eight weeks. The training aimed to introduce the basic principles of letter-speech sound correspondences and to initialize the sensitization of specific brain areas to print. Event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) data were recorded during an explicit word/symbol processing task after the training. Reading skills were assessed two years later in second grade. The focus of this study was on clarifying whether electrophysiological and fMRI data of kindergarten children significantly improve prediction of future reading skills in 2nd grade over behavioural data alone. Based on evidence from previous studies demonstrating the importance of initial print sensitivity in the left occipito-temporal visual word form system (VWFS) for learning to read, the first pronounced difference in processing words compared to symbols in the ERP, an occipito-temporal negativity (N1: 188-281 ms) along with the corresponding functional activation in the left occipito-temporal VWFS were defined as potential predictors. ERP and fMRI data in kindergarteners significantly improved the prediction of reading skills in 2nd grade over behavioural data alone. Together with the behavioural measures they explained up to 88% of the variance. An additional discriminant analysis revealed a remarkably high accuracy in classifying normal (n=11) and poor readers (n=6). Due to the key limitation of the study, i.e. the small group sizes, the results of our prediction analyses should be interpreted with caution and regarded as preliminary despite cross-validation. Nevertheless our results indicate the potential of combining neuroimaging and behavioural measures to improve prediction at an early stage, when literacy skills are acquired and interventions are most beneficial.

The ventral occipitotemporal (vOT) cortex serves as a core region for visual processing, and specific areas of this region show preferential activation for various visual categories such as faces and print. The emergence of such functional specialization in the human cortex represents a pivotal developmental process, which provides a basis for targeted and efficient information processing. For example, functional specialization to print in the left vOT is an important prerequisite for fluent reading. However, it remains unclear, which processes initiate the preferential cortical activations to characters arising in the vOT during child development. Using a multimodal neuroimaging approach with preschool children at familial risk for developmental dyslexia, we demonstrate how varying levels of expertise modulate the neural response to single characters, which represent the building blocks of print units. The level of expertise to characters was manipulated firstly through brief training of false-font speech-sound associations and secondly by comparing characters for which children differed in their level of familiarity and expertise accumulated through abundant exposure in their everyday environment. Neural correlates of character processing were tracked with simultaneous high-density electroencephalography and functional magnetic resonance imaging in a target detection task. We found training performance and expertise-dependent modulation of the visual event-related potential around 220 ms (N1) and the corresponding vOT activation. Additionally, trained false-font characters revealed stronger functional connectivity between the left fusiform gyrus (FFG) seed and left superior parietal/lateral occipital cortex regions with higher training performance. In sum, our results demonstrate that learning artificial-character speech-sound associations enhances activation to trained characters in the vOT and that the magnitude of this activation and the functional connectivity of the left FFG to the parieto-occipital cortex depends on learning performance. This pattern of results suggests emerging development of the reading network after brief training that parallels network specialization during reading acquisition.

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

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

Phonological awareness refers to the ability to perceive and manipulate the sound structure of language and is especially important when children learn to read. Poor phonological awareness is considered the major cause for the emergence of reading difficulties. In this functional magnetic resonance imaging (fMRI) study, we examined the brain correlates of phonological processing in young beginning readers (aged 8.3+/-0.4 y, 2nd grade) with poor (<25th percentile) or normal, age-appropriate reading skills (>40th percentile) using a covert reading and mental letter substitution task. Letter substitution in words and nonwords induced pronounced activity in a left frontal language network related to phonological processing, with maxima in the left inferior frontal gyrus and in the insula. The activation within this frontal network increased with better reading skills and differentiated between normal and poor reading young children. Lateralization indices of overall frontal activity for normal and poor readers pointed to stronger left hemispheric involvement in normal readers as compared to the more bilateral activation pattern in poor readers. To summarize, young children with age-appropriate reading skills display a left hemispheric dominance characteristic for language processing already by grade two. The more bilateral activation pattern in poor readers points to an increased effort and the emergence of compensatory strategies for reading and phonological processing just 1.5 years after the start of formal reading instruction.

A consistent finding in functional brain imaging studies of reading with dyslexia is reduced inferior occipito-temporal activation linked to deviant processing of visual word forms. Time-sensitive event-related potentials (ERP) further revealed reduced inferior occipito-temporal N1 tuning for print in dyslexic 2nd graders suggesting the reduction affects fast processing and the initial development of dyslexia. Here, we followed up the same groups with ERP recordings and investigated how fast print tuning deficits in dyslexia develop from 2nd to 5th grade. Using functional magnetic resonance imaging (fMRI), we further characterized spatial aspects of print tuning in the 5th grade. The robust N1 tuning deficit for print in the dyslexic 2nd graders had largely disappeared by grade 5 consistent with a developmental delay. Reduced word-specific activation in dyslexic 5th grader's fMRI data occurred bilaterally in middle temporal regions and in the left posterior superior sulcus. Although no group differences in inferior occipito-temporal regions appeared in the whole brain analysis, a region of interest analysis of the Visual Word Form Area revealed that control children showed a more lateralized word-specific activation pattern than the children with dyslexia. The results suggest that while impaired N1 tuning for print plays a major role for dyslexia at the beginning of learning to read, other aspects of visual word form processing in the same region remain impaired in dyslexic children after several years of reading practice. Overall, neural deficits associated with dyslexia appear to be plastic and to change throughout development and reading acquisition.

Developmental dyslexia is a severe reading disorder, which is characterized by dysfluent reading and impaired automaticity of visual word processing. Adults with dyslexia show functional deficits in several brain regions including the so-called "Visual Word Form Area" (VWFA), which is implicated in visual word processing and located within the larger left occipitotemporal VWF-System. The present study examines functional connections of the left occipitotemporal VWF-System with other major language areas in children with dyslexia. Functional connectivity MRI was used to assess connectivity of the VWF-System in 18 children with dyslexia and 24 age-matched controls (age 9.7-12.5 years) using five neighboring left occipitotemporal regions of interest (ROIs) during a continuous reading task requiring phonological and orthographic processing. First, the results revealed a focal origin of connectivity from the VWF-System, in that mainly the VWFA was functionally connected with typical left frontal and parietal language areas in control children. Adjacent posterior and anterior VWF-System ROIs did not show such connectivity, confirming the special role that the VWFA plays in word processing. Second, we detected a significant disruption of functional connectivity between the VWFA and left inferior frontal and left inferior parietal language areas in the children with dyslexia. The current findings add to our understanding of dyslexia by showing that functional disconnection of the left occipitotemporal system is limited to the small VWFA region crucial for automatic visual word processing, and emerges early during reading acquisition in children with dyslexia, along with deficits in orthographic and phonological processing of visual word forms.

The classical phonological deficit account of dyslexia is increasingly linked to impairments in grapho-phonological conversion, and to dysfunctions in superior temporal regions associated with audiovisual integration. The present study investigates mechanisms of audiovisual integration in typical and impaired readers at the critical developmental stage of adolescence. Congruent and incongruent audiovisual as well as unimodal (visual only and auditory only) material was presented. Audiovisual presentations were single letters and three-letter (consonant-vowel-consonant) stimuli accompanied by matching or mismatching speech sounds. Three-letter stimuli exhibited fast phonetic transitions as in real-life language processing and reading. Congruency effects, i.e. different brain responses to congruent and incongruent stimuli were taken as an indicator of audiovisual integration at a phonetic level (grapho-phonological conversion). Comparisons of unimodal and audiovisual stimuli revealed basic, more sensory aspects of audiovisual integration. By means of these two criteria of audiovisual integration, the generalizability of audiovisual deficits in dyslexia was tested. Moreover, it was expected that the more naturalistic three-letter stimuli are superior to single letters in revealing group differences. Electrophysiological and hemodynamic (EEG and fMRI) data were acquired simultaneously in a simple target detection task. Applying the same statistical models to event-related EEG potentials and fMRI responses allowed comparing the effects detected by the two techniques at a descriptive level. Group differences in congruency effects (congruent against incongruent) were observed in regions involved in grapho-phonological processing, including the left inferior frontal and angular gyri and the inferotemporal cortex. Importantly, such differences also emerged in superior temporal key regions. Three-letter stimuli revealed stronger group differences than single letters. No significant differences in basic measures of audiovisual integration emerged. Convergence of hemodynamic and electrophysiological signals appeared to be limited and mainly occurred for highly significant and large effects in visual cortices. The findings suggest efficient superior temporal tuning to audiovisual congruency in controls. In impaired readers, however, grapho-phonological conversion is effortful and inefficient, although basic audiovisual mechanisms seem intact. This unprecedented demonstration of audiovisual deficits in adolescent dyslexics provides critical evidence that the phonological deficit might be explained by impaired audiovisual integration at a phonetic level, especially for naturalistic and word-like stimulation.

Abilities to discriminate forms defined by motion continue to develop throughout childhood. To investigate late development of the visual motion system, we measured brain activity with event-related EEG potentials (ERPs) and functional magnetic resonance imaging (fMRI) in groups of adolescents (15-17 years) and adults (20-30 years) during a visual form discrimination task--with forms being either defined by motion or luminance contrast. We further explored whether possible developmental changes varied with the degree of motion coherence reflecting maturation specific to global motion processing. Both the fMRI activation patterns and ERP topographies were very similar between adolescents and adults, suggesting that the basic visual networks for processing motion and form are established by the age of 15-17. The ERP response to luminance- and motion-defined forms was dominated by a posterior negativity (N1: 120-270 ms). The N1 of the motion contrast was delayed in adolescents, whereas the N1 of the static condition did not differ between groups. Since the motion-evoked N1 is thought to arise in the middle temporal area MT/V5, our results indicate that visual motion processing in MT continues to get faster, becoming still more efficient during late development. Neither the ERP nor the fMRI results revealed maturation effects specific to motion coherence. This indicates that the specific mechanisms to process global dot motion are already mature in adolescence. The present findings support the view that static perception matures earlier than dynamic perception, and that these visual systems have different developmental courses.

Developmental dyslexia is a specific disorder of reading acquisition characterized by a phonological core deficit. Sentence reading is also impaired in dyslexic readers, but whether semantic processing deficits contribute is unclear. Combining spatially and temporally sensitive neuroimaging techniques to focus on semantic processing can provide a more comprehensive characterization of sentence reading in dyslexia. We recorded brain activity from 52 children (16 with dyslexia, 31 controls) with functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) in two separate counterbalanced sessions. The children silently read and occasionally judged simple sentences with semantically congruous or incongruous endings. fMRI and ERP activation during sentence reading and semantic processing was analyzed across all children and also by comparing children with dyslexia to controls. For sentence reading, we analyzed the response to all words in a sentence; for semantic processing, we contrasted responses to incongruous and congruous endings. Sentence reading was characterized by activation in a left-lateralized language network. Semantic processing was characterized by activation in left-hemispheric regions of the inferior frontal and superior temporal cortex and by an electrophysiological N400 effect after 240 ms with consistent left anterior source localization. Children with dyslexia showed decreased activation for sentence reading in inferior parietal and frontal regions, and for semantic processing in inferior parietal regions, and during the N400 effect. Together, this suggests that semantic impairment during sentence reading reduces dyslexic children's response in left anterior brain regions underlying the more phasic N400 effect and subsequently modulates the more sustained BOLD response in left inferior parietal regions.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive-compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = -0.21, z = -3.21, p = 0.001) and posterior thalamic radiation (d = -0.26, z = -4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = -2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = -1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.

Objective: Brain imaging communities focusing on different diseases have increasingly started to collaborate and to pool data to perform well-powered meta- and mega-analyses. Some methodologists claim that a one-stage individual-participant data (IPD) mega-analysis can be superior to a two-stage aggregated data meta-analysis, since more detailed computations can be performed in a mega-analysis. Before definitive conclusions regarding the performance of either method can be drawn, it is necessary to critically evaluate the methodology of, and results obtained by, meta- and mega-analyses. Methods: Here, we compare the inverse variance weighted random-effect meta-analysis model with a multiple linear regression mega-analysis model, as well as with a linear mixed-effects random-intercept mega-analysis model, using data from 38 cohorts including 3,665 participants of the ENIGMA-OCD consortium. We assessed the effect sizes and standard errors, and the fit of the models, to evaluate the performance of the different methods. Results: The mega-analytical models showed lower standard errors and narrower confidence intervals than the meta-analysis. Similar standard errors and confidence intervals were found for the linear regression and linear mixed-effects random-intercept models. Moreover, the linear mixed-effects random-intercept models showed better fit indices compared to linear regression mega-analytical models. Conclusions: Our findings indicate that results obtained by meta- and mega-analysis differ, in favor of the latter. In multi-center studies with a moderate amount of variation between cohorts, a linear mixed-effects random-intercept mega-analytical framework appears to be the better approach to investigate structural neuroimaging data.

The level of reading skills in children and adults is reflected in the strength of preferential neural activation to print. Such preferential activation appears in the N1 event-related potential (ERP) over the occipitotemporal scalp after around 150-250 ms and the corresponding blood oxygen level dependent (BOLD) signal in the ventral occipitotemporal (vOT) cortex. Here, orthography-sensitive (print vs. false font) processing was examined using simultaneous EEG-fMRI in 38 first grade children with poor and typical reading skills, and at varying familial risk for developmental dyslexia. Coarse orthographic sensitivity was observed as an increased activation to print in the N1 ERP and in the BOLD signal of individually varying vOT regions in 57% of beginning readers. Finer differentiation in processing orthographic strings (words vs. nonwords) further occurred in specific vOT clusters. Neither method alone showed robust differences in orthography-sensitive processing between typical and poor reading children. Importantly, using single-trial N1 ERP-informed fMRI analysis, we found differential modulation of the orthography-sensitive BOLD response in the left vOT for typical readers only. This result, thus, confirms subtle functional alterations in a brain structure known to be critical for fluent reading at the very beginning of reading instruction.

During reading acquisition, neural reorganization of the human brain facilitates the integration of letters and speech sounds, which enables successful reading. Neuroimaging and behavioural studies have established that impaired audiovisual integration of letters and speech sounds is a core deficit in individuals with developmental dyslexia. This longitudinal study aimed to identify neural and behavioural markers of audiovisual integration that are related to future reading fluency. We simulated the first step of reading acquisition by performing artificial-letter training with prereading children at risk for dyslexia. Multiple logistic regressions revealed that our training provides new precursors of reading fluency at the beginning of reading acquisition. In addition, an event-related potential around 400 ms and functional magnetic resonance imaging activation patterns in the left planum temporale to audiovisual correspondences improved cross-validated prediction of future poor readers. Finally, an exploratory analysis combining simultaneously acquired electroencephalography and hemodynamic data suggested that modulation of temporoparietal brain regions depended on future reading skills. The multimodal approach demonstrates neural adaptations to audiovisual integration in the developing brain that are related to reading outcome. Despite potential limitations arising from the restricted sample size, our results may have promising implications both for identifying poor-reading children and for monitoring early interventions.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Late development of specialization in the visual word processing system was examined using event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) of word and symbol string processing in groups of adolescents (15.2-17.3 years) and adults (19.8-30.8 years). We focused our ERP analyses on fast visual activity: the occipital P1 (82-131 ms) modulated by physical stimulus characteristics and the occipito-temporal N1 (132-256 ms) reflecting visual tuning for print. Our fMRI analyses concentrated on basal occipito-temporal activations in the visual word form area VWFA. For words, the correlation of fMRI activation in the VWFA and N1 amplitude confirmed the close relationship of the electrophysiological N1 with metabolic activity in the VWFA. Further support for this relationship came from low resolution electromagnetic tomography localizing the word-specific N1 near the VWFA. Both imaging techniques revealed age-independent differences between words and symbol strings. Late development, however, was preferentially detected with ERPs. Decreases of P1 and N1 amplitudes with age were not limited to words and suggested further maturation of the underlying brain microstructure and function. Following adolescence, decreasing N1 latencies specific to words point to continued specialization of the visual word processing system. Both N1 and fMRI measures correlated with reading performance. In summary, the similarity of global fMRI activation patterns between groups suggests a fully established distribution of the reading network in adolescence, while the decreasing N1 latencies for words indicate protracted fine tuning after adolescence.

Changes in response contingencies require adjusting ones assumptions about outcomes of behaviors. Such adaptation processes are driven by reward prediction error (RPE) signals which reflect the inadequacy of expectations. Signals resembling RPEs are known to be encoded by mesencephalic dopamine neurons projecting to the striatum and frontal regions. Although regions that process RPEs, such as the dorsal anterior cingulate cortex (dACC), have been identified, only indirect evidence links timing and network organization of RPE processing in humans. In electroencephalography (EEG), which is well known for its high temporal resolution, the feedback-related negativity (FRN) has been suggested to reflect RPE processing. Recent studies, however, suggested that the FRN might reflect surprise, which would correspond to the absolute, rather than the signed RPE signals. Furthermore, the localization of the FRN remains a matter of debate. In this simultaneous EEG-functional magnetic resonance imaging (fMRI) study, we localized the FRN directly using the superior spatial resolution of fMRI without relying on any spatial constraint or other assumption. Using two different single-trial approaches, we consistently found a cluster within the dACC. One analysis revealed additional activations of the salience network. Furthermore, we evaluated the effect of signed RPEs and surprise signals on the FRN amplitude. We considered that both signals are usually correlated and found that only surprise signals modulate the FRN amplitude. Last, we explored the pathway of RPE signals using dynamic causal modeling (DCM). We found that the surprise signals are directly projected to the source region of the FRN. This finding contradicts earlier theories about the network organization of the FRN, but is in line with a recent theory stating that dopamine neurons also encode surprise-like saliency signals. Our findings crucially advance the understanding of the FRN. We found compelling evidence that the FRN originates from the dACC. Furthermore, we clarified the functional role of the FRN, and determined the role of the dACC within the RPE network. These findings should enable us to study the processing of surprise and adjustment signals in the dACC in healthy and also in psychiatric patients.