Reading-FREE Markers for Early Detection of Developmental Dyslexia

Official title

Longitudinal Assessment of Multidomain Reading-FREE Neurocognitive Markers for Early Detection of Developmental Dyslexia (FREE-DD)

Overview

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.

Detailed description

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.

Interventions

• Behavioral Multidomain Neuropsychological and Reading-Free Screening Tool (RSFT) Assessment Battery - Grade 2
  * Behavioral testing: standardized neuropsychological battery (language, reading, attention, memory, intelligence) * RFST: Reading-Free Screening Tool assessing pre-reading cognitive markers
• Diagnostic test MRI - Grade 2
  ■ Diagnostic Imaging: structural and resting-state functional MRI (T1-weighted and rs-fMRI)
• Behavioral Multidomain Neuropsychological and Reading-Free Screening Tool (RSFT) Assessment Battery - Grade 3
  * Behavioral testing: standardized neuropsychological battery (language, reading, attention, memory, intelligence) * RFST: Reading-Free Screening Tool assessing pre-reading cognitive markers

Primary outcome measures

• Change in RFST Auditory Modality Composite Score From Grade 2 to Grade 3 in Preterm Children [Time frame: From Grade 2 baseline to Grade 3 follow-up assessment (approx. 8-10 months)]
• Change in RFST Visual Modality Composite Score From Grade 2 to Grade 3 in Preterm Children [Time frame: From Grade 2 baseline to Grade 3 follow-up assessment (approx. 8-10 months)]
• Grade 2 Composite Language Score in Preterm Children [Time frame: Grade 2 baseline assessment]
• Grade 2 Composite Attention Score in Preterm Children [Time frame: Grade 2 baseline assessment]
• Grade 2 Composite Reading Score in Preterm Children [Time frame: Grade 2 baseline assessment]
• Grade 2 Resting-State fMRI Network Segregation Score in Preterm Children [Time frame: Grade 2 baseline MRI session]
• Grade 2 Resting-State fMRI Network Integration Score in Preterm Children [Time frame: Grade 2 baseline MRI session]

Secondary outcome measures (3)

• Language Score at Grade 3 in Preterm Children [Time frame: Grade 3 follow-up assessment]
• Composite Attention Score at Grade 3 in Preterm Children [Time frame: Grade 3 follow-up assessment (8-10 months post-baseline)]
• Composite Reading Score at Grade 3 in Preterm Children [Time frame: Grade 3 follow-up assessment]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Screening

Study locations

Italy · 1 center

• Neuroradiology Unit and CERMAC, IRCCS Ospedale San Raffaele — Milan

Publications

• Canini, M., Cara, C., Oprandi, C., Katušić, A., Žunić Išasegi, I., Messina, A., Zambon, A. A., Pecco, N., Barni, S., Poloniato, A., Natali Sora, M. G., Falautano, M., Scifo, P., Barera, G., Tettamanti, M., Falini, A., Baldoli, C., & Della Rosa, P. A. (2025). Functional connectivity markers of prematurity at birth predict neurodevelopmental outcomes at 6, 12, 24, and 36 months. International Journa
• Della Rosa PA, Canini M, Marchetta E, Cirillo S, Pontesilli S, Scotti R, Natali Sora MG, Poloniato A, Barera G, Falini A, Scifo P, Baldoli C. The effects of the functional interplay between the Default Mode and Executive Control Resting State Networks on cognitive outcome in preterm born infants at 6 months of age. Brain Cogn. 2021 Feb;147:105669. doi: 10.1016/j.bandc.2020.105669. Epub 2020 Dec 17 PMID 33341657
• Baldoli C, Scola E, Della Rosa PA, Pontesilli S, Longaretti R, Poloniato A, Scotti R, Blasi V, Cirillo S, Iadanza A, Rovelli R, Barera G, Scifo P. Maturation of preterm newborn brains: a fMRI-DTI study of auditory processing of linguistic stimuli and white matter development. Brain Struct Funct. 2015 Nov;220(6):3733-51. doi: 10.1007/s00429-014-0887-5. Epub 2014 Sep 23. PMID 25244942
• Carioti D, Stucchi NA, Toneatto C, Masia MF, Del Monte M, Stefanelli S, Travellini S, Marcelli A, Tettamanti M, Vernice M, Guasti MT, Berlingeri M. The ReadFree tool for the identification of poor readers: a validation study based on a machine learning approach in monolingual and minority-language children. Ann Dyslexia. 2023 Oct;73(3):356-392. doi: 10.1007/s11881-023-00287-3. Epub 2023 Aug 7. PMID 37548832

Identifiers

NCT: NCT07072104 · CET 501-2024 · PRIN - Prot. 2022TA92HS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗