Increased Coupling in the Saliency Network is the main cause/effect of Attention Deficit Hyperactivity Disorder (1112.3496v1)

Abstract: To uncover the underlying mechanisms of mental disorders such as attention deficit hyperactivity disorder (ADHD) for improving both early diagnosis and therapy, it is increasingly recognized that we need a better understanding of how the brain's functional connections are altered. A new brain wide association study (BWAS) has been developed and used to investigate functional connectivity changes in the brains of patients suffering from ADHD using resting state fMRI data. To reliably find out the most significantly altered functional connectivity links and associate them with ADHD, a meta-analysis on a cohort of ever reported largest population comprising 249 patients and 253 healthy controls is carried out. The greatest change in ADHD patients was the increased coupling of the saliency network involving the anterior cingulate gyrus and anterior insula. A voxel-based morphometry analysis was also carried out but this revealed no evidence in the ADHD patients for altered grey matter volumes in the regions showing altered functional connectivity. This is the first evidence for the involvement of the saliency network in ADHD and it suggests that this may reflect increased sensitivity over the integration of the incoming sensory information and his/her own thoughts and the network as a switch is bias towards to the central executive network.

• The paper presents a brain-wide association study (BWAS) on large ADHD cohorts, revealing significantly increased coupling within the salience network, especially between the anterior cingulate and insula.
• Key findings highlight that brain connectivity changes in ADHD are predominantly found in links between different functional communities rather than within them, suggesting network-wide alterations.
• The study supports the hypothesis that altered salience network dynamics, acting as a switch between brain states, may underlie attention deficits in ADHD and demonstrates a novel BWAS method applicable to other disorders.

The paper presents an advanced analysis of functional connectivity changes in individuals with Attention Deficit Hyperactivity Disorder (ADHD) using a newly developed brain-wide association paper (BWAS) approach leveraging resting-state functional magnetic resonance imaging (rs-fMRI) data. This paper is positioned as a notable expansion over traditional methods, such as seed-based and Independent Component Analysis (ICA), by offering an unbiased framework to identify key pathway modifications without predefining focal regions or assuming brain independence.

Study Overview:

• Cohort Description: The analysis was conducted on a large cohort, comprising 249 ADHD patients and 253 healthy controls, sourced from the largest populations documented in ADHD research to date, specifically from Peking University and New York University datasets.
• Methodology: The BWAS approach is analogous to genome-wide association studies (GWAS) in that it evaluates the statistical significance of connectivity alterations by associating modified functional links with the disorder. The paper uses rigorous statistical corrections, including Bonferroni and False Discovery Rate (FDR), to mitigate false positives resulting from multiple comparisons.

Key Findings:

1. Altered Salience Network Coupling: The most prominent discovery is the enhanced coupling within the salience network, particularly between the anterior cingulate gyrus (ACG) and anterior insula (AI) in the left hemisphere of ADHD patients. This enhanced connectivity suggests increased sensitivity to sensory stimuli and internal thought processes, potentially biasing attention towards the central executive network.
2. Inter-Community Connectivity: Significant alterations were identified predominantly in inter-community links, rather than intra-community ones, indicating broad network-level changes rather than localized disruptions. This reinforces the understanding of ADHD as a complex neurobehavioral disorder with network-wide brain changes affecting cognitive processes.
3. Voxel-Based Morphometry (VBM): Despite functional connectivity changes, VBM analysis did not show significant reductions in gray matter volume among the altered regions, suggesting functional alterations are not driven by structural abnormalities in these regions.
4. Auxiliary Link Changes: Beyond the salience network, additional links such as those between the orbitofrontal cortex (ORBmed) and the precuneus gyrus (PCG), and between the temporal pole (TPOSup), were found to exhibit significant alterations. These may suggest additional ADHD-related dysregulations within cognitive and sensory processing pathways.

Interpretations and Implications:

• Salience Network Role in ADHD: The paper corroborates the concept that the salience network acts as a dynamic switch influencing the balance between the default mode network (DMN) and the central executive network. This enhanced connectivity in ADHD patients supports the hypothesis that this network may play a critical role in attention modulation and executive dysfunction inherent to ADHD.
• Broader Implications: While specifically investigating ADHD, the BWAS approach can be adapted for exploring other psychiatric, developmental, or neurodegenerative disorders, providing valuable insights into disorder-specific connectivity patterns and associated neurobiological mechanisms.

Conclusion:

This work presents a substantial contribution to understanding ADHD by unambiguously identifying altered salience network dynamics as likely integral to the disorder's pathophysiology. These findings highlight the importance of focusing on network-level interactions and comprehensive approaches in neuropsychiatric research to enhance diagnostic and therapeutic strategies. The potential translation of this methodological advancement to a wider range of mental health disorders marks a promising avenue for future research.