Emotion dysregulation and right pars orbitalis constitute a neuropsychological pathway to ADHD

333 

Abstract Submission 

Wenjie Hou¹, Barbara Sahakian^2,3, Christelle Langley^2,3, Yuqing Yang⁴, Richard Bethlehem⁵, Qiang Luo^6,7,8,9,10

¹State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science and Research Institute of Intelligent Complex Systems, Fudan University, Shang Hai, China, ²Departments of Psychiatry, University of Cambridge, Cambridge, United Kingdom, ³Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom, ⁴New York University Shanghai, Shang Hai, China, ⁵Department of Psychology, University of Cambridge, Cambridge, United Kingdom, ⁶Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shang Hai, China, ⁷Human Phenome Institute, Fudan University, Shang Hai, China, ⁸MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Shang Hai, China, ⁹School of Life Sciences, Fudan University, Shang Hai, China, ¹⁰National Clinical Research Center for Aging and Medicine at Huashan Hospital, Fudan University, Shang Hai, China

Wenjie Hou  
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science and Research Institute of Intelligent Complex Systems, Fudan University
Shang Hai, China

Barbara Sahakian  
Departments of Psychiatry, University of Cambridge|Behavioural and Clinical Neuroscience Institute, University of Cambridge
Cambridge, United Kingdom|Cambridge, United Kingdom

Christelle Langley  
Departments of Psychiatry, University of Cambridge|Behavioural and Clinical Neuroscience Institute, University of Cambridge
Cambridge, United Kingdom|Cambridge, United Kingdom

Yuqing Yang  
New York University Shanghai
Shang Hai, China

Richard Bethlehem  
Department of Psychology, University of Cambridge
Cambridge, United Kingdom

Qiang Luo  
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University|Human Phenome Institute, Fudan University|MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University|School of Life Sciences, Fudan University|National Clinical Research Center for Aging and Medicine at Huashan Hospital, Fudan University
Shang Hai, China|Shang Hai, China|Shang Hai, China|Shang Hai, China|Shang Hai, China

Attention-deficit/hyperactivity disorder (ADHD) affects 5.9%-7.1% of children and adolescents1 and is characterized by its clinical heterogeneity in symptoms and their trajectories2. Theoretical models, such as the dual-pathway model (i.e., the cognitive and the motivational pathways)3, have long been hypothesized to explain this heterogeneity4. However, both cognitive impairment and motivational dysfunction can be absent in about 30% of the ADHD cases5, and cannot predict the different clinical trajectories of the ADHD symptoms (e.g., the persistent or the remitting trajectories)6. Emotion dysregulation, characterized by difficulties with both awareness and regulation of emotion, has been associated with more severe and persistent ADHD symptoms and might be a key component of the self-regulation deficits in ADHD7. As yet, however, it remains unclear whether emotion dysregulation, independent of cognition and motivation, contributes to the symptom heterogeneity in ADHD as a unique pathway.
Neuroimaging studies have shown that the cognitive and the motivational pathways mainly associated with the fronto-dorsal striatal and the fronto-ventral striatal circuits, respectively3. However, the neuroimaging features of these brain circuits explain only a limited proportion of the heterogeneity in ADHD symptoms (ΔR^2=0.008)4. Whereas, the emotion dysregulation has been mainly associated with the fronto-limbic circuitry8, which overlaps with many brain regions known to be associated with ADHD9. Therefore, we hypothesized that the emotion dysregulation may represent a third neuropsychological pathway to ADHD, which is separable from the cognitive and motivational pathways3,4. Advanced knowledge on the role of emotion dysregulation in ADHD may be valuable for identifying individuals at risk for persistent ADHD symptoms.

Participants: The discovery sample included 6,053 adolescents of 12 years from the Adolescent Brain Cognitive Development (ABCD) study. Emotion dysregulation, cognitive function and motivational dysfunction were assessed. The replication sample consisted of 263 patients with ADHD and 409 healthy controls. Structural brain images, genetic, transcriptomic, and blood white cell counts data were obtained.
Main outcome measures: Parents were assessed for the adolescents' ADHD symptoms by Child Behavior Checklist.
Design: Linear mixed-effect model and causal Bayesian network analyses were conducted to assess the associations between emotion dysregulation problems and both ADHD symptoms and structural neuroimaging features while controlling for both the cognitive and the motivational dysfunctions and medical treatment for ADHD. Longitudinal mediation analysis was used to establish the pathway from brain through emotion dysregulation to ADHD, which validated using the clinical sample. Transcriptomic analysis was performed to identify biological pathways unique to the emotion pathway.

Using a large population-based cohort (n=6,053) we showed that the emotion dysregulation was associated with ADHD symptoms (partial eta2=0.21) and their persistence after controlling for the cognitive and the motivational deficits. The emotion dysregulation mediated the association between the smaller surface area of the right pars orbitalis and greater ADHD symptoms at a one-year follow-up, indicating an emotion pathway to ADHD. Notably, we found that the emotion pathway was uniquely associated with immune responses through transcriptome analysis, and that more emotion regulation problems and smaller right pars orbitalis surface area were also associated with polygenic risk score for ADHD in the ABCD European samples. Finally, we validated the emotion pathway using another clinical sample for ADHD (n=672).

In summary, we have shown using a large sample and a second independent sample that emotion dysregulation is a core symptom and a route to ADHD, which may not respond to the current pharmacological treatments for ADHD.

Neurodevelopmental/ Early Life (eg. ADHD, autism) ¹

Transcriptomics

Early life, Adolescence, Aging ²

Other - Attention-deficit/hyperactivity disorder; Heterogeneity; The dual-pathway model; Emotion dysregulation pathway; Immune function