Weakened effective connectivity between salience network and default mode network during resting state in adolescent depression.

Adolescent major depressive disorder (MDD) is associated with altered resting-state connectivity between the default mode network (DMN) and the salience network (SN), which are involved in self-referential processing and detecting and filtering salient stimuli, respectively. Using spectral dynamical causal modelling, we investigated the effective connectivity and input sensitivity between key nodes of these networks in 30 adolescents with MDD and 32 healthy controls while undergoing resting-state fMRI. We found that the DMN received weaker inhibition from the SN and that the medial prefrontal cortex and the anterior cingulate cortex showed reduced self-inhibition in MDD, making them more prone to external influences. Moreover, we found that selective serotonin reuptake inhibitor (SSRI) intake was associated with decreased and increased self-inhibition of the SN and DMN, respectively, in patients. Our findings suggest that adolescent MDD is characterized by a hierarchical imbalance between the DMN and the SN, which could affect the integration of emotional and self-related information. We propose that SSRIs may help restore network function by modulating excitatory/inhibitory balance in the DMN and the SN. Our study highlights the potential of prefrontal-amygdala interactions as a biomarker and a therapeutic target for adolescent depression.

Unraveling individual differences in learning potential: A dynamic framework for the case of reading development.

Children show an enormous capacity to learn during development, but with large individual differences in the time course and trajectory of learning and the achieved skill level. Recent progress in developmental sciences has shown the contribution of a multitude of factors including genetic variation, brain plasticity, socio-cultural context and learning experiences to individual development. These factors interact in a complex manner, producing children's idiosyncratic and heterogeneous learning paths. Despite an increasing recognition of these intricate dynamics, current research on the development of culturally acquired skills such as reading still has a typical focus on snapshots of children's performance at discrete points in time. Here we argue that this 'static' approach is often insufficient and limits advancements in the prediction and mechanistic understanding of individual differences in learning capacity. We present a dynamic framework which highlights the importance of capturing short-term trajectories during learning across multiple stages and processes as a proxy for long-term development on the example of reading. This framework will help explain relevant variability in children's learning paths and outcomes and fosters new perspectives and approaches to study how children develop and learn.

The odd one out - Orthographic oddball processing in children with poor versus typical reading skills in a fast periodic visual stimulation EEG paradigm.

The specialization of left ventral occipitotemporal brain regions to automatically process word forms develops with reading acquisition and is diminished in children with poor reading skills (PR). Using a fast periodic visual oddball stimulation (FPVS) design during electroencephalography (EEG), we examined the level of sensitivity and familiarity to word form processing in ninety-two children in 2nd and 3rd grade with varying reading skills (n = 35 for PR, n = 40 for typical reading skills; TR). To test children's level of "sensitivity", false font (FF) and consonant string (CS) oddballs were embedded in base presentations of word (W) stimuli. "Familiarity" was examined by presenting letter string oddballs with increasing familiarity (CS, pseudoword - PW, W) in FF base stimuli. Overall, our results revealed stronger left-hemispheric coarse sensitivity effects ("FF in W" > "CS in W") in TR than in PR in both topographic and oddball frequency analyses. Further, children distinguished between orthographically legal and illegal ("W/PW in FF" > "CS in FF") but not yet between lexical and non-lexical ("W in FF" vs "PW in FF") word forms. Although both TR and PR exhibit visual sensitivity and can distinguish between orthographically legal and illegal letter strings, they still struggle with nuanced lexical distinctions. Moreover, the strength of sensitivity is linked to reading proficiency. Our work adds to established knowledge in the field to characterize the relationship between print tuning and reading skills and suggests differences in the developmental progress to automatically process word forms.

White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

Self-regulation of visual word form area activation with real-time fMRI neurofeedback.

The Visual Word Form Area (VWFA) is a key region of the brain's reading network and its activation has been shown to be strongly associated with reading skills. Here, for the first time, we investigated whether voluntary regulation of VWFA activation is feasible using real-time fMRI neurofeedback. 40 adults with typical reading skills were instructed to either upregulate (UP group, N = 20) or downregulate (DOWN group, N = 20) their own VWFA activation during six neurofeedback training runs. The VWFA target region was individually defined based on a functional localizer task. Before and after training, also regulation runs without feedback ("no-feedback runs") were performed. When comparing the two groups, we found stronger activation across the reading network for the UP than the DOWN group. Further, activation in the VWFA was significantly stronger in the UP group than the DOWN group. Crucially, we observed a significant interaction of group and time (pre, post) for the no-feedback runs: The two groups did not differ significantly in their VWFA activation before neurofeedback training, but the UP group showed significantly stronger activation than the DOWN group after neurofeedback training. Our results indicate that upregulation of VWFA activation is feasible and that, once learned, successful upregulation can even be performed in the absence of feedback. These results are a crucial first step toward the development of a potential therapeutic support to improve reading skills in individuals with reading impairments.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

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.

Disentangling influences of dyslexia, development, and reading experience on effective brain connectivity in children.

Altered brain connectivity between regions of the reading network has been associated with reading difficulties. However, it remains unclear whether connectivity differences between children with dyslexia (DYS) and those with typical reading skills (TR) are specific to reading impairments or to reading experience. In this functional MRI study, 132 children (M = 10.06 y, SD = 1.46) performed a phonological lexical decision task. We aimed to disentangle (1) disorder-specific from (2) experience-related differences in effective connectivity and to (3) characterize the development of DYS and TR. We applied dynamic causal modeling to age-matched (ndys = 25, nTR = 35) and reading-level-matched (ndys = 25, nTR = 22) groups. Developmental effects were assessed in beginning and advanced readers (TR: nbeg = 48, nadv = 35, DYS: nbeg = 24, nadv = 25). We show that altered feedback connectivity between the inferior parietal lobule and the visual word form area (VWFA) during print processing can be specifically attributed to reading impairments, because these alterations were found in DYS compared to both the age-matched and reading-level-matched TR. In contrast, feedforward connectivity from the VWFA to parietal and frontal regions characterized experience in TR and increased with age and reading skill. These directed connectivity findings pinpoint disorder-specific and experience-dependent alterations in the brain's reading network.

Visual Occipito-Temporal N1 Sensitivity to Digits Across Elementary School.

Number processing abilities are important for academic and personal development. The course of initial specialization of ventral occipito-temporal cortex (vOTC) sensitivity to visual number processing is crucial for the acquisition of numeric and arithmetic skills. We examined the visual N1, the electrophysiological correlate of vOTC activation across five time points in kindergarten (T1, mean age 6.60 years), middle and end of first grade (T2, 7.38 years; T3, 7.68 years), second grade (T4, 8.28 years), and fifth grade (T5, 11.40 years). A combination of cross-sectional and longitudinal EEG data of a total of 62 children (35 female) at varying familial risk for dyslexia were available to form groups of 23, 22, 27, 27, and 42 participants for each of the five time points. The children performed a target detection task which included visual presentation of single digits (DIG), false fonts (FF), and letters (LET) to derive measures for coarse (DIG vs. FF) and fine (DIG vs. LET) digit sensitive processing across development. The N1 amplitude analyses indicated coarse and fine sensitivity characterized by a stronger N1 to digits than false fonts across all five time points, and stronger N1 to digits than letters at all but the second (T2) time point. In addition, lower arithmetic skills were associated with stronger coarse N1 digit sensitivity over the left hemisphere in second grade (T4), possibly reflecting allocation of more attentional resources or stronger reliance on the verbal system in children with poorer arithmetic skills. To summarize, our results show persistent visual N1 sensitivity to digits that is already present early on in pre-school and remains stable until fifth grade. This pattern of digit sensitivity development clearly differs from the relatively sharp rise and fall of the visual N1 sensitivity to words or letters between kindergarten and middle of elementary school and suggests unique developmental trajectories for visual processing of written characters that are relevant to numeracy and literacy.

Associations of medication with subcortical morphology across the lifespan in OCD: Results from the international ENIGMA Consortium.

BACKGROUND: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. METHODS: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. RESULTS: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31). CONCLUSIONS: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

Deficient prefrontal-amygdalar connectivity underlies inefficient face processing in adolescent major depressive disorder.

Adolescence represents a critical developmental period where the prevalence of major depressive disorder (MDD) increases. Aberrant emotion processing is a core feature of adolescent MDD that has been associated with functional alterations within the prefrontal-amygdala circuitry. In this study, we tested cognitive and neural mechanisms of emotional face processing in adolescents with MDD utilizing a combination of computational modeling and neuroimaging. Thirty adolescents with MDD (age: M = 16.1 SD = 1.4, 20 females) and 33 healthy controls (age: M = 16.2 SD = 1.9, 20 females) performed a dynamic face- and shape-matching task. A linear ballistic accumulator model was fit to the behavioral data to study differences in evidence accumulation. We used dynamic causal modeling (DCM) to study effective connectivity in the prefrontal-amygdala network to reveal the neural underpinnings of cognitive impairments while performing the task. Face processing efficiency was reduced in the MDD group and most pronounced for ambiguous faces with neutral emotional expressions. Critically, this reduction was related to increased deactivation of the subgenual anterior cingulate (sgACC). Connectivity analysis showed that MDD exhibited altered functional coupling in a distributed network spanning the fusiform face area-lateral prefrontal cortex-sgACC and the sgACC-amygdala pathway. Our results suggest that MDD is related to impairments of processing nuanced facial expressions. Distributed dysfunctional coupling in the face processing network might result in inefficient evidence sampling and inappropriate emotional responses contributing to depressive symptomatology. Our study provides novel insights in the characterization of brain function in adolescents with MDD that strongly emphasize the critical role of aberrant prefrontal-amygdala interactions during emotional face processing.

Virtual Ontogeny of Cortical Growth Preceding Mental Illness.

BACKGROUND: 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. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

The thalamus and its subnuclei-a gateway to obsessive-compulsive disorder.

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.

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Maladaptive Avoidance Learning in the Orbitofrontal Cortex in Adolescents With Major Depression.

BACKGROUND: Understanding the mechanisms in the brain's incentive network that give rise to symptoms of major depressive disorder (MDD) during adolescence provides new perspectives to address MDD in early stages of development. This functional magnetic resonance imaging study determines whether instrumental vigor and brain responses to appetitive and aversive monetary incentives are altered in adolescent MDD and associated with symptom severity. METHODS: Adolescents with moderate to severe MDD (n = 30, mean age [SD] = 16.1 [1.4] years) and healthy control subjects (n = 33, mean age = 16.2 [1.9] years) matched for age, sex, and IQ performed a monetary incentive delay task. During outcome presentation, prediction error signals were used to study the response and coupling of the incentive network during learning of cue-outcome associations. A computational reinforcement model was used to assess adaptation of response vigor. Brain responses and effective connectivity to model-derived prediction errors were assessed and related to depression severity and anhedonia levels. RESULTS: Participants with MDD behaved according to a more simplistic learning model and exhibited slower learning. Effective connectivity analysis of functional magnetic resonance imaging data revealed that impaired loss error processing in the orbitofrontal cortex was associated with aberrant gain control. Anhedonia scores correlated with loss-related error signals in the posterior insula and habenula. CONCLUSIONS: Adolescent MDD is selectively related to impaired processing of error signals during loss, but not reward, in the orbitofrontal cortex. Aberrant evaluation of loss outcomes might reflect an early mechanism of how negative bias and helplessness manifest in the brain. This approach sheds light on pathomechanisms in MDD and may improve early diagnosis and treatment selection.

Developmental Trajectories of Letter and Speech Sound Integration During Reading Acquisition.

Reading acquisition in alphabetic languages starts with learning the associations between speech sounds and letters. This learning process is related to crucial developmental changes of brain regions that serve visual, auditory, multisensory integration, and higher cognitive processes. Here, we studied the development of audiovisual processing and integration of letter-speech sound pairs with an audiovisual target detection functional MRI paradigm. Using a longitudinal approach, we tested children with varying reading outcomes before the start of reading acquisition (T1, 6.5 yo), in first grade (T2, 7.5 yo), and in second grade (T3, 8.5 yo). Early audiovisual integration effects were characterized by higher activation for incongruent than congruent letter-speech sound pairs in the inferior frontal gyrus and ventral occipitotemporal cortex. Audiovisual processing in the left superior temporal gyrus significantly increased from the prereading (T1) to early reading stages (T2, T3). Region of interest analyses revealed that activation in left superior temporal gyrus (STG), inferior frontal gyrus and ventral occipitotemporal cortex increased in children with typical reading fluency skills, while poor readers did not show the same development in these regions. The incongruency effect bilaterally in parts of the STG and insular cortex at T1 was significantly associated with reading fluency skills at T3. These findings provide new insights into the development of the brain circuitry involved in audiovisual processing of letters, the building blocks of words, and reveal early markers of audiovisual integration that may be predictive of reading outcomes.

Psilocybin Induces Aberrant Prediction Error Processing of Tactile Mismatch Responses-A Simultaneous EEG-FMRI Study.

As source of sensory information, the body provides a sense of agency and self/non-self-discrimination. The integration of bodily states and sensory inputs with prior beliefs has been linked to the generation of bodily self-consciousness. The ability to detect surprising tactile stimuli is essential for the survival of an organism and for the formation of mental body representations. Despite the relevance for a variety of psychiatric disorders characterized by altered body and self-perception, the neurobiology of these processes is poorly understood. We therefore investigated the effect of psilocybin (Psi), known to induce alterations in self-experience, on tactile mismatch responses by combining pharmacological manipulations with simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) recording. Psi reduced activity in response to tactile surprising stimuli in frontal regions, the visual cortex, and the cerebellum. Furthermore, Psi reduced tactile mismatch negativity EEG responses at frontal electrodes, associated with alterations of body- and self-experience. This study provides first evidence that Psi alters the integration of tactile sensory inputs through aberrant prediction error processing and highlights the importance of the 5-HT2A system in tactile deviancy processing as well as in the integration of bodily and self-related stimuli. These findings may have important implications for the treatment of psychiatric disorders characterized by aberrant bodily self-awareness.

Neurodevelopment of the incentive network facilitates motivated behaviour from adolescence to adulthood.

The ability to enhance motivated performance through incentives is crucial to guide and ultimately optimise the outcome of goal-directed behaviour. It remains largely unclear how motivated behaviour and performance develops particularly across adolescence. Here, we used computational fMRI to assess how response speed and its underlying neural circuitry are modulated by reward and loss in a monetary incentive delay paradigm. We demonstrate that maturational fine-tuning of functional coupling within the cortico-striatal incentive circuitry from adolescence to adulthood facilitates the ability to enhance performance selectively for higher subjective values. Additionally, during feedback, we found developmental sex differences of striatal representations of reward prediction errors in an exploratory analysis. Our findings suggest that a reduced capacity to utilise subjective value for motivated behaviour in adolescence is rooted in immature information processing in the incentive system. This indicates that the neurocircuitry for coordination of incentivised, motivated cognitive control acts as a bottleneck for behavioural adjustments in adolescence.

The rise and fall of rapid occipito-temporal sensitivity to letters: Transient specialization through elementary school.

Letters, foundational units of alphabetic writing systems, are quintessential to human culture. The ability to read, indispensable to perform in today's society, necessitates a reorganization of visual cortex for fast letter recognition, but the developmental course of this process has not yet been characterized. Here, we show the emergence of visual sensitivity to letters across five electroencephalography measurements from kindergarten and throughout elementary school and relate this development to emerging reading skills. We examined the visual N1, the electrophysiological correlate of ventral occipito-temporal cortex activation in 65 children at varying familial risk for dyslexia. N1 letter sensitivity emerged in first grade, when letter sound knowledge gains were most pronounced and decayed shortly after when letter knowledge is consolidated, showing an inverted U-shaped development. This trajectory can be interpreted within an interactive framework that underscores the influence of top-down predictions. While the N1 amplitudes to letters correlated with letter sound knowledge at the beginning of learning, no association between the early N1 letter response and later reading skills was found. In summary, the current findings provide an important reference point for our neuroscientific understanding of learning trajectories and the process of visual specialization during skill learning.