This study aims to identify early signs of developmental dyslexia (DD) and other reading difficulties in children born preterm, using behavioral, cognitive, and brain imaging data collected before reading problems typically become noticeable. Children born very early often face greater risk for reading and learning challenges, but these difficulties are not always detected in time for early support. This research seeks to fill that gap. A group of 30 children born preterm will be followed over time, alongside a control group of 15 children born at term. All children will be assessed during the second and third years of primary school (around ages 6-9). In Grade 2, children will undergo (a) a specially designed digital screening tool for reading difficulties that does not require actual reading (called the RFST), (b) standard tests of reading, language, and attention, and (c) structural and functional brain scans using Magnetic Resonance Imaging (MRI). In Grade 3, the children will be reassessed using the RFST and the cognitive and language tests. The goal is to identify specific behavioral and brain-based markers-particularly patterns of brain connectivity-that are already present in Grade 2 and can predict which children will go on to show reading difficulties in Grade 3. By comparing data from preterm and term-born children, researchers aim to discover early warning signs that are specific to children born preterm. By detecting these risks early, before reading delays become severe, the study hopes to guide new tools for screening and early intervention, tailored specifically to the unique developmental paths of children born preterm. This could help prevent later academic struggles and promote better long-term outcomes.

This longitudinal study, titled "Longitudinal assessment of multidomain reading-FREE neurocognitive markers for early detection of Developmental Dyslexia (FREE-DD)", investigates early neurocognitive predictors of developmental dyslexia (DD) and related reading disorders in children born preterm (PTB), as compared to children born at term (ATB). Children born preterm are at elevated risk for neurodevelopmental vulnerabilities, including difficulties with language, attention, and reading acquisition, yet early identification of these risks remains limited.

The main objective of the study is to identify early connectomic and neurocognitive markers-obtained during second grade-that can predict the development of reading difficulties in PTB children by third grade. Particular emphasis is placed on connectomic features derived from functional and structural brain imaging, as well as on a specially designed behavioral tool: the Reading-Free Screening Tool (RFST), which assesses reading-related cognitive abilities without requiring the child to read.

The study adopts a prospective, longitudinal, monocentric cohort design, with two assessment waves:

• Grade 2 (Baseline/Timepoint 1): All enrolled children will undergo a comprehensive neuropsychological battery, RFST administration, and MRI acquisition (including structural and resting-state functional MRI).
• Grade 3 (Follow-up/Timepoint 2): Children will be reassessed using the RFST and neuropsychological tests to track changes in cognitive and reading-related abilities.

The study population includes 30 preterm-born (PTB) children and 15 term-born (ATB) children, all aged between 6 and 9 years, native Italian speakers, and right-handed. Children with structural brain lesions, congenital anomalies, or known neurological/psychiatric conditions will be excluded.

Primary Objective The primary goal is to determine whether functional brain network characteristics (measured via resting-state fMRI), along with morpho-structural, microstructural, and cognitive metrics collected at grade 2, can predict changes in RFST performance and reading skills between grade 2 and grade 3.

Secondary Objectives

Secondary aims include:

• Assessing correlations between functional connectivity and RFST indices.
• Evaluating whether measures of brain network segregation and integration can classify PTB vs. ATB readers and forecast individual developmental trajectories.
• Identifying multimodal predictors of atypical reading profiles across both grades.

Exploratory Objectives The study also seeks to explore the role of combined behavioral and neuroimaging data in outlining early neurocognitive trajectories specific to prematurity, which may indicate susceptibility to developmental dyslexia and related disorders. These exploratory outcomes will help refine developmental models and screening strategies.

Methodology

Participants will complete:

• Parental questionnaires (screening and developmental history),
• Manual preference testing,
• Two waves of neuropsychological assessments targeting language, attention, memory, phonological processing, and non-verbal intelligence,
• RFST administration,
• MRI scanning (T1-weighted structural imaging and resting-state fMRI). Data Analysis

Analysis will proceed in three main steps:

1. Functional Connectivity Mapping: Correlating ROI-to-ROI functional brain connectivity with RFST indices across all participants.
2. Group Classification: Extracting graph-based network metrics (e.g., segregation, integration) to classify PTB vs. ATB participants.
3. Predictive Modeling (PTB group): Employing the most relevant imaging and behavioral features to predict changes in RFST performance between grades 2 and 3, modeling individual developmental outcomes.

Timeline and Duration

• Enrollment Period: 2 months
• Total Participant Commitment: Approx. 4 hours (2 hours per visit across two school years)
• Study Duration: 10-12 months (including follow-up) This study is sponsored by the Università Vita-Salute San Raffaele and funded by PRIN (Progetti di Ricerca di Rilevante Interesse Nazionale - Bando 2022, Prot. 2022TA92HS). It will be conducted at the clinical center of the Ospedale San Raffaele (OSR), under the direction of the U.O. of Neuroradiology.

The findings from this study aim to inform the development of screening tools and targeted early interventions for children born preterm, potentially reducing the long-term impact of developmental dyslexia and enhancing academic and cognitive outcomes.

Inclusion Criteria:

For Preterm-Born (PTB) Children:

• Born preterm (i.e., gestational age < 39 weeks)
• Aged between 6 and 9 years at enrollment
• Absence of structural brain lesions (as assessed by prior clinical imaging)
• Italian as the first language (L1)
• Right-hand dominant
• Male or female

For At-Term-Born (ATB) Children:

• Born at term (i.e., gestational age between 39 and 42 weeks)
• Aged between 6 and 9 years at enrollment
• Absence of structural brain lesions (as assessed by prior clinical imaging)
• Italian as the first language (L1)
• Right-hand dominant
• Male or female

Exclusion Criteria:

For Preterm-Born (PTB) Children:

• History of congenital infections
• Diagnosis of Multiple Congenital Anomalies Syndrome
• Presence of focal intracerebral parenchymal lesions
• Pathological findings on conventional MRI

For At-Term-Born (ATB) Children:

• Presence of first-degree relatives diagnosed with developmental dyslexia (DD)
• Diagnosis of other learning or behavioral disorders
• Contraindications to MRI (e.g., metal implants, severe claustrophobia)