Aug 2026· Biological Psychiatry: Cognitive Neuroscience and Neuroimaging· 0 citations· 73 references
Medicine
TL;DR
This narrative review integrates existing evidence on the developmental delay hypothesis to help focus future efforts, while highlighting current challenges and potential solutions to inspire innovative directions for research into the neurodevelopmental mechanisms underlying ADHD.
Abstract
Attention deficit hyperactivity disorder (ADHD) is hypothesized to be associated with delayed brain maturation rather than atypical brain development. While this developmental delay hypothesis has gained widespread recognition, research progress has stagnated, and the field lacks a consolidated overview of existing findings and challenges. This narrative review integrates multi-dimensional findings across behavioral manifestations, electroencephalography (EEG), structural,diffusion, and functional magnetic resonance imaging (MRI), and genetics, supporting a regionally specific and multi-trajectory heterogeneous delay model. Based on a critical discussion of the literature and recent advancements, four critical unresolved challenges are identified: (1) incomplete explanatory power of delay phenomena; (2) whether temporal delays lead to reduced peak amplitudes in developmental trajectories; (3) whether delayed trajectories can achieve developmental "catch-up" prior to brain maturation; and (4) heterogeneity in delayed developmental pathways. To address these challenges, we propose four strategies: (1) establishing longitudinal high-density tracking cohorts; (2) constructing multimodal brain-age prediction models; (3) identifying neurodevelopmental delay subtypes through heterogeneity modeling; and (4) quantifying ADHD-related developmental delays via disease progression modeling. These approaches aim to lay a foundation for precise diagnosis, treatment, and early intervention in ADHD. This review integrates existing evidence on the developmental delay hypothesis to help focus future efforts, while highlighting current challenges and potential solutions to inspire innovative directions for research into the neurodevelopmental mechanisms underlying ADHD.
Studies on the Mirror Neuron System (MNS), a network activated during both action execution and observation, suggest a key role in several functions. Although present from early postnatal life, its maturation across developmental stages remains unclear, as does its vulnerability to adverse conditions such as early brain injury or Neurodevelopmental Disorders affecting action planning, execution, and imitation. To better understand MNS development along the continuum from typical to atypical trajectories, a systematic review was conducted. The work, carried out in January 2026 across multiple databases, identified three main findings. First, the MNS is active in early infancy but becomes increasingly specialised and lateralised with development, influenced by goal-directed actions, social context, and motor experience. Second, the network appears to be susceptible to atypical neurodevelopmental processes, as evidenced by different activations in specific Neurodevelopmental Disorders, such as Developmental Coordination Disorder and Autism Spectrum Disorder, although findings are conflicting, or as shown by studies in children with Cerebral Palsy, in whom different activations are generally observed. Third, preliminary evidence suggests a link between rehabilitation outcomes and MNS-related neuroplasticity, particularly in Action Observation Treatment for children with Cerebral Palsy. The present systematic review serves as a first step in enhancing the importance of furthering knowledge of the evolution and peculiarities of MNS in children. Understanding how this system develops, adapts and changes in response to experience can have fundamental implications for clinical and rehabilitation purposes.
Scrocco Antea, Ferragina Francesca, Bianucci Carolina et al.· Neuroscience and Biobehavior...· 0 citations
The evidence suggests that myelin-related pathways represent a common point of vulnerability across disorders and may offer a potential target for intervention, integrating findings from both animal models and human research.
Justyna Lubińska, Maya Śliwa, Małgorzata Filip et al.· Current Neuropharmacology· 0 citations
Adolescent obesity has emerged as a global public health crisis, with accumulating evidence suggesting that it involves not only peripheral metabolic dysfunction but also significant central nervous system remodeling. Given that childhood and adolescence represent a critical window for neurodevelopment, understanding these alterations is vital for effective intervention. This review aimed to systematically synthesize multimodal magnetic resonance imaging (MRI) findings regarding brain structural and functional changes in children and adolescents with obesity, and its underlying neurobiological mechanisms.
Following PRISMA guidelines, there were in total 41 high-quality studies encompassing functional MRI, structural MRI, and diffusion tensor imaging modalities involved in this review.
Synthesis of the literature reveals a consistent “reward-control” imbalance. Functionally, adolescents with obesity exhibited hyper-responsivity in reward-related regions (e.g., striatum, insula) to food cues, coupled with diminished recruitment of executive control areas (e.g., prefrontal cortex). Structurally, obesity was associated with gray matter atrophy in the prefrontal and cingulate cortices, and lower white matter integrity in tracts connecting these regions (e.g., corpus callosum, uncinate fasciculus). These changes may be associated with a synergy of chronic neuroinflammation, insulin resistance, and dopamine pathway dysregulation, although the cross-sectional nature of most evidence precludes definitive causal inferences.
Obesity-related brain remodeling constitutes a pathological basis that reinforces maladaptive eating behaviors. Future research should prioritize longitudinal designs and targeted neuro-interventions to mitigate long-term cognitive and metabolic consequences in children and adolescent with obesity.
Hui Xu, Junshen Zhang, Yang Wang et al.· Frontiers in Human Neuroscie...· 0 citations
Neurodevelopmental disorders are defined within a developmental framework, yet diagnostic reasoning in clinical practice still relies largely on observations made at a single time point. This creates a tension: intervention is expected early, while diagnostic validity depends on how difficulties evolve over time. We argue that this tension reflects a limited integration of time into diagnostic reasoning. In the absence of validated biomarkers, clinical manifestations are not static. They emerge from interactions between brain maturation, environmental demands, and compensatory processes. Their meaning depends on how they change over time and respond to intervention. This perspective calls for a better account of developmental variability and the heterogeneity of trajectories, particularly in childhood. During this period, expectations change rapidly, and differences in maturation may lead to divergent interpretations of similar behaviors. Executive functions are discussed as one illustrative developmental marker because of their prolonged maturation, transdiagnostic nature, and sensitivity to contextual demands. Diagnosis is therefore better understood not as a one-time decision, but as a process grounded in developmental trajectories. Longitudinal observation, including repeated assessments and changes in response to structured environmental adjustments, provides critical information to distinguish transient developmental difficulties from more persistent neurodevelopmental constraints. This framework has implications for both clinical practice and research. It supports early identification and intervention, while emphasizing the need for structured longitudinal monitoring and stronger integration of temporal dynamics into diagnostic models. In neurodevelopment, diagnosis is not the reading of a state, but the interpretation of a trajectory.
Bertrand Schoentgen· Frontiers in Neuroscience· 0 citations
We reviewed longitudinal magnetic resonance imaging (MRI) studies exploring the brain development of children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we conducted a systematic review of papers published until 9 September 2025 in English on pediatric patients with ADHD. After screening 3385 studies, 32 were selected for review. The age range at baseline for the participants in the review ranged from 4 to 18 years old. Children with ADHD exhibited delays in brain volume and cortical thickness compared to typically developing (TD) children, particularly at baseline, with these differences often persisting over time, with four key trends. First, children with ADHD showed smaller cerebral and cerebellar volumes, with no significant changes in their developmental trajectories. Second, there was a delayed peak in the cortical thickness, surface area, and gyrification observed in regions such as the prefrontal, temporal, and occipital gyri for children with ADHD. Third, the differences in brain volume and cortical thickness between ADHD and TD children diminished with age, particularly in the cerebellar white matter and caudate. Finally, ADHD children showed atypical growth patterns such as contraction of the ventral striatum surface area. A meta-analysis of longitudinal changes in total gray matter volume revealed no significant differences between children with ADHD and TD peers. Due to inconsistencies across studies and methodological challenges in integrating these findings, the results should be interpreted with caution. Selection bias is another concern. Multicenter studies with standardized protocols, long-term follow-ups, considering gender, comorbidities, and medication effects are required to enhance study replicability.
Ayaka Ishii-Takahashi, Yuzu Yoshimaru, D. Muhammad et al.· Psychiatry and Clinical Neur...· 0 citations
Attention-deficit/hyperactivity disorder (ADHD) is characterized by a continuum of symptoms, including inattentiveness, impulsiveness, and hyperactivity, which can negatively impact daily life. In laboratory settings, these deficits are manifested as increased reaction-time variability in continuous performance tasks (CPTs) over several minutes. Although considerable work has elucidated neural mechanisms associated with ADHD, less is known about how these mechanisms vary across the continuum of symptom severity. We investigated whether symptom severity could be explained in the Extended Brain Criticality framework. Brains operate in an extended critical regime between disorder (asynchronous) and order (synchronous) at balanced excitation-inhibition which is characterized by moderate synchronization and scale-free long-range temporal correlations (LRTCs) across hundreds of seconds. We hypothesized that differences in brain operating points (brain states) along the critical-like regime and paralleled changes in LRTCs could predict ADHD symptom continuum. We measured brain activity with magnetoencephalography (MEG) during rest and two CPTs from adult ADHD and control participants and assessed criticality with LRTCs of neuronal oscillations. LRTCs showed high variability, but overall ADHD patients exhibited stronger LRTCs than NC in low (5-20 Hz) and high (30-100 Hz) frequencies as well as stronger task effects. ADHD symptom severity was predicted by individual variability in LRTCs and i.e., by the individual's position in the critical phase with both linear and quadratic correlations such that the severity of symptoms were predicted by shifts of the operating point toward the supercritical direction in a frequency dependent manner. Our study thus proposes a novel complex systems-level framework to explain the emergence of ADHD symptoms and their continuum across the population.
H. Haque, Jonni Hirvonen, Sheng H. Wang et al.· Translational Psychiatry· 0 citations
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