Attention Deficit Hyperactivity Disorder (ADHD), a neurodevelopmental disorder characterized by pervasive inattention, hyperactivity, and impulsivity, has long been associated with abnormal brain connectivity patterns. However, the intricate ways in which these connectivity alterations present across different spatial scales in the brain have remained largely elusive. In a groundbreaking study recently published in Nature Mental Health, Gao, Zhou, Bao, and colleagues address this critical knowledge gap by applying advanced neuroimaging analytic techniques to resting-state functional MRI (fMRI) data. Their work reveals a multiscale imbalance in the functional connectivity between higher-order cognitive and lower-order sensory networks in children and adolescents with ADHD.
The study analyzed resting-state fMRI data from an extensive cohort of 454 children and adolescents, encompassing both those diagnosed with ADHD and typically developing controls. Importantly, the data were aggregated from three independent cohorts to enhance statistical power and generalizability. The authors systematically dissected ADHD-related functional connectivity anomalies at three hierarchical levels: global, region-to-region, and network-level scales. This multiscale approach allowed for a nuanced characterization of the dysconnectivity associated with ADHD, illuminating how aberrations manifest both broadly across the brain and within specific network circuits.
At the global level, the investigation uncovered a distinctive pattern of hypoconnectivity, particularly localized in hubs of the default mode network (DMN) as well as in visual processing regions. The DMN, known for its central role in self-referential thought and mind-wandering, serves as a critical nexus in the brain’s intrinsic architecture. Its hubs typically exhibit dense connectivity facilitating higher-order cognitive functions. The observed diminished connectivity within these hubs in individuals with ADHD marks a significant departure from typical brain function, suggesting impaired integrative processes fundamental to attention and cognitive control. Hypoconnectivity in visual areas further points to disruptions in sensory integration, potentially underpinning the sensory processing difficulties reported clinically in ADHD.
On a finer spatial scale, the authors applied region-to-region connectivity analyses to unravel more specific circuit-level abnormalities. This examination revealed pronounced hypoconnectivity within the DMN itself, affirming the global findings but with greater anatomical specificity. Additionally, hypoconnectivity was evident between key DMN hubs and visual regions, indicating reduced coordination between internal cognitive networks and external sensory input. Beyond the DMN-visual axis, hypoconnectivity also manifested between nodes of the salience network (SAN) and frontoparietal networks on one side, and auditory/sensorimotor areas on the other. This finding exposes a crucial disruption in communication between high-order attention and cognitive control networks and those involved in auditory processing and sensorimotor integration.
Remarkably, the region-to-region analysis also exposed a concurrent pattern of hyperconnectivity, particularly linking the DMN with the salience network, frontoparietal networks, and auditory regions. This suggests that while some connections are weakened, others become excessively coupled, potentially compensatory or maladaptive. The hyperconnectivity between the DMN and attention-related networks may reflect an abnormal intertwining of internal thought processes and external cognitive control mechanisms, possibly contributing to the hallmark inattentiveness and hyperactivity observed in ADHD.
Taking a step back to examine network-level interactions, the authors identified persistent hypoconnectivity between the salience network and auditory/sensorimotor regions, underscoring the robustness of this finding across scales. However, intriguingly, at this coarser level, the DMN alterations that were so prominent at other scales no longer reached significance. This observation suggests that the dysconnectivity within the DMN in ADHD might be highly localized and nuanced, detectable only when analyzed at higher spatial resolutions. Such scale-dependent differences underscore the necessity of multilevel analyses to fully capture the complexity of brain network pathology in neurodevelopmental disorders.
A notable strength of this study lies in its rigorous investigation of potential confounds. The authors conducted comprehensive analyses to determine whether ADHD-associated connectivity alterations varied by age or sex. Their results demonstrated that these functional connectivity disruptions were consistent across developmental stages and between males and females, reinforcing the idea that these neural changes reflect core pathophysiological mechanisms of ADHD. However, medication status and comorbid psychiatric conditions significantly influenced the observed connectivity patterns, highlighting the importance of considering pharmacological and clinical heterogeneity in neuroimaging studies of ADHD.
The implications of these findings extend beyond descriptive accounts of connectivity abnormalities. The demonstration of an imbalanced interplay between higher-order cognitive networks—such as the DMN, salience network, and frontoparietal control network—and lower-order sensory networks provides a compelling neurobiological substrate for the multifaceted symptomatology of ADHD. The deficits in coordination between these networks may manifest clinically as difficulties in sustaining attention, heightened distractibility, and impaired sensorimotor gating, which are characteristic hallmarks of the disorder.
Methodologically, the authors employed state-of-the-art neuroimaging techniques combined with network neuroscience principles to yield high-resolution insights. Resting-state fMRI presents an optimal avenue for investigating intrinsic brain connectivity without confounds of task performance. By leveraging large-scale data and sophisticated analytic frameworks, including multiscale connectivity modeling, Gao et al. circumvented limitations of prior smaller studies often constrained by sample size and analytic depth. Their integrative strategy sets a new benchmark for understanding brain network dysfunction in ADHD and other neurodevelopmental disorders.
Furthermore, the study’s revelations concerning scale-dependent dysconnectivity enrich ongoing debates about the hierarchical organization of brain networks and how neurodevelopmental disorders perturb this delicate spatial architecture. The differences between global, region-to-region, and network-level findings emphasize that aberrant connectivity in ADHD cannot be fully explained by analyses conducted at a single scale. Instead, dynamic interactions and compensatory mechanisms likely operate across multiple spatial dimensions, complicating the clinical phenotype and response to treatment.
Clinically, the identification of hypoconnectivity between the salience network and auditory/sensorimotor regions points to potential targets for therapeutic intervention. Modulation of these circuits through neurostimulation or targeted cognitive training could restore functional balance and alleviate core symptoms. Similarly, the documented hyperconnectivity between DMN and other higher-order networks invites further exploration into whether reducing maladaptive over-coupling might enhance cognitive control and reduce distractibility.
The study’s nuanced findings regarding medication effects also deserve emphasis. The observed modulation of connectivity alterations depending on medication status provides neurobiological evidence supporting the impact of pharmacotherapy on brain network dynamics. This insight aligns with prior studies indicating that stimulant medications can normalize some aspects of functional connectivity in ADHD, underscoring the value of personalized treatment approaches informed by neuroimaging biomarkers.
In sum, the work by Gao and colleagues represents a significant advance in our understanding of ADHD-related brain dysconnectivity. By embracing a multiscale analytic lens, the authors elucidate the complex interplay between higher-order cognitive and lower-order sensory networks that underpin functional impairments in ADHD. Their findings pave the way for future research to parse the causal mechanisms linking network-level alterations to clinical manifestations and to develop novel intervention strategies that precisely target dysfunctional circuitry.
Ultimately, this study serves as a clarion call to the psychiatric and neuroscience communities to adopt integrative, scale-sensitive perspectives when investigating brain connectivity in neurodevelopmental disorders. The intricate balance between global coordination and local specialization emerges as a vital principle, disruption of which may hold the key to unlocking new therapeutic avenues for ADHD and beyond.
Subject of Research:
Functional brain connectivity in Attention Deficit Hyperactivity Disorder (ADHD)
Article Title:
Multiscale functional connectivity reveals imbalanced interplay between higher- and lower-order brain networks in ADHD
Article References:
Gao, Y., Zhou, Z., Bao, W. et al. Multiscale functional connectivity reveals imbalanced interplay between higher- and lower-order brain networks in ADHD. Nat. Mental Health (2025). https://doi.org/10.1038/s44220-025-00512-5
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