Accumulating evidence suggests that functional Near-Infrared Spectroscopy (fNIRS) can provide an essential bridge between our current understanding of neural circuit organization and cortical activity in the developing brain. Indeed, fNIRS allows studying brain functions through the measurement of neurovascular coupling that links neural activity to subsequent changes in cerebral blood flow and hemoglobin oxygenation levels. While the literature offers a multitude of fNIRS applications to typical development, only recently this tool has been extended to the study of neurodevelopmental disorders (NDDs). The exponential rise of scientific publications on this topic during the last years reflects the interest to identify a “fNIRS signature” as a biomarker of high translational value to support both early clinical diagnosis and treatment outcome. The purpose of this systematic review is to describe the updating clinical applications of fNIRS in NDDs, with a specific focus on preschool population. Starting from this rationale, a systematic search was conducted for relevant studies in different scientific databases (Pubmed, Scopus, and Web of Science) resulting in 13 published articles. In these studies, fNIRS was applied in individuals with Autism Spectrum Disorder (ASD) or infants at high risk of developing ASD. Both functional connectivity in resting-state conditions and task-evoked brain activation using multiple experimental paradigms were used in the selected investigations, suggesting that fNIRS might be considered a promising method for identifying early quantitative biomarkers in the autism field.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, the underlying pathological mechanisms of which are not yet completely understood. Although several genetic and genomic alterations have been linked to ASD, for the majority of ASD patients, the cause remains unknown, and the condition likely arises due to complex interactions between low-risk genes and environmental factors. There is increasing evidence that epigenetic mechanisms that are highly sensitive to environmental factors and influence gene function without altering the DNA sequence, particularly aberrant DNA methylation, are involved in ASD pathogenesis. This systematic review aimed to update the clinical application of DNA methylation investigations in children with idiopathic ASD, investigating its potential application in clinical settings. To this end, a literature search was performed on different scientific databases using a combination of terms related to the association between peripheral DNA methylation and young children with idiopathic ASD; this search led to the identification of 18 articles. In the selected studies, DNA methylation is investigated in peripheral blood or saliva samples, at both gene-specific and genome-wide levels. The results obtained suggest that peripheral DNA methylation could represent a promising methodology in ASD biomarker research, although further studies are needed to develop DNA-methylation-based clinical applications.

A quantitative biomarker for myelination, such as myelin water fraction (MWF), would boost the understanding of normative and pathological neurodevelopment, improving patients' diagnosis and follow‐up. We quantified the fraction of a rapidly relaxing pool identified as MW using multicomponent three‐dimensional (3D) magnetic resonance fingerprinting (MRF) to evaluate white matter (WM) maturation in typically developing (TD) children and alterations in leukodystrophies (LDs). We acquired DTI and 3D MRF‐based R1, R2 and MWF data of 15 TD children and 17 LD patients (9 months–12.5 years old) at 1.5 T. We computed normative maturation curves in corpus callosum and corona radiata and performed WM tract profile analysis, comparing MWF with R1, R2 and fractional anisotropy (FA). Normative maturation curves demonstrated a steep increase for all tissue parameters in the first 3 years of age, followed by slower growth for MWF while R1, R2R₂ and FA reached a plateau. Unlike FA, MWF values were similar for regions of interest (ROIs) with different degrees of axonal packing, suggesting independence from fiber bundle macro‐organization and higher myelin specificity. Tract profile analysis indicated a specific spatial pattern of myelination in the major fiber bundles, consistent across subjects. LD were better distinguished from TD by MWF rather than FA, showing reduced MWF with respect to age‐matched controls in both ROI‐based and tract analysis. In conclusion, MRF‐based MWF provides myelin‐specific WM maturation curves and is sensitive to alteration due to LDs, suggesting its potential as a biomarker for WM disorders. As MRF allows fast simultaneous acquisition of relaxometry and MWF, it can represent a valuable diagnostic tool to study and follow up developmental WM disorders in children.

Autism spectrum disorder (ASD) refers to a neurodevelopmental condition whose detection still remains challenging in young females due to the heterogeneity of the behavioral phenotype and the capacity of camouflage. The availability of quantitative biomarkers to assess brain function may support in the assessment of ASD. Functional Near-infrared Spectroscopy (fNIRS) is a non-invasive and flexible tool that quantifies cortical hemodynamic responses (HDR) that can be easily employed to describe brain activity. Since the study of the visual phenotype is a paradigmatic model to evaluate cerebral processing in many neurodevelopmental conditions, we hypothesized that visually-evoked HDR (vHDR) might represent a potential biomarker in ASD females. We performed a case-control study comparing vHDR in a cohort of high-functioning preschooler females with ASD (fASD) and sex/age matched peers. We demonstrated the feasibility of visual fNIRS measurements in fASD, and the possibility to discriminate between fASD and typical subjects using different signal features, such as the amplitude and lateralization of vHDR. Moreover, the level of response lateralization was correlated to the severity of autistic traits. These results corroborate the cruciality of sensory symptoms in ASD, paving the way for the validation of the fNIRS analytical tool for diagnosis and treatment outcome monitoring in the ASD population.

Neurodevelopmental disorders (NDDs) cause profound intellectual and physical impairment, yet therapeutic progress remains hindered by the lack of quantitative, unbiased, and non-invasive biomarkers to monitor disease onset and progression. Visual evoked potentials (VEPs) have emerged as promising functional biomarkers for X-linked NDDs, with reduced VEP amplitudes correlating with disease severity. Complementary approaches, like functional Near Infrared Spectroscopy (fNIRS), offer a non-invasive additional tool to assess brain metabolism, monitor disease progression, and evaluate therapeutic responses. This perspective explores the potential of fNIRS in studying visually evoked hemodynamic responses (vHDR) across different age groups, demonstrating its reliability in capturing task-specific cortical activation and tracking brain maturation even in challenging populations. Notably, fNIRS identifies unique vHDR patterns in conditions like optic neuritis, myopia, glaucoma, and migraines, validating its role as a biomarker for disease severity and treatment efficacy. Moreover, fNIRS has proven effective in detecting early neural deficits in high-risk infants, including pre-term newborns. Preclinical studies support that visually induced hemodynamic changes can differentiate healthy from pathological conditions in X-linked NDDs. However, direct evidence from human cohorts with X-linked NDDs remains limited, highlighting the urgent need for further research to validate the potential of visual fNIRS as a reliable functional biomarker in clinical settings. To enhance clinical relevance, the development of standardized protocols, engaging stimuli, and age-stratified analyses is also crucial for improving diagnostic accuracy, tracking neurodevelopmental trajectories, and evaluating therapeutic interventions.