LAUSR

Background ADHD is the most common childhood-onset psychiatric disorder, affecting 5% of children. Costing over 7 bn $CAD annually, ADHD has broad negative impacts on the individual and society. Psychostimulants are effective in managing symptoms and implicate the catecholamine systems. ADHD is heterogeneous and arises by complex interplay of genetic and environmental factors. Despite the high heritability of ADHD (76%), causal genes have yet to be determined. A linkage study by our team uncovered a modest over transmittance of NET16 (rs36021) in ADHD children. Interestingly, upon stratification according to maternal smoking during pregnancy (MSDP), this result became highly significant in exposed children. Our findings indicate that MSDP plays a role in the etiology of ADHD, possibly through interaction with NET16. To shed light on the pathophysiology of ADHD, we used MRI to explore the impact of this interaction on cortical structures in children with ADHD. Methods We began by modelling the effects of (1) MSDP, (2) NET16, and (3) both MSDP and NET16 on the cortex. Subjects (n=143; 6–12 years) were recruited from an on-going clinical trial at the ADHD clinic. Genetic, epigenetic, environmental, cognitive, clinical and structural data were collected. Subjects were scanned on a 3 T Siemens MRI for 18 minutes to obtain T1/T2-weighted images. To address motion biases and minimize procedural failures, children rehearsed on a mock scanner and only scans that passed quality control were used in the analysis (n=111). CIVET-1.1.12 and RMINC were used to acquire cortical measurements and perform linear modelling. We included age, sex, medication, NET16 genotype group and MSDP as predictors, and cortical measurements as main outcome measures. Results (1) Our first model found no significant differences in cortical thickness among ADHD children exposed and not exposed to MSDP. (2) Our second model showed a moderate effect of NET16 genotype group on cortical thickness. Children belonging to the homozygous groups (AA, TT) had significant reductions in cortical thickness in the medial/inferior prefrontal cortex and the left inferior temporal lobe (t=2.46; 10% FDR) vs. children in the heterozygote group (AT). These regions have been previously associated with ADHD, where the PFC plays a role in executive functioning and the temporal lobes work alongside the amygdala to enable learning, memory and emotional responses. (3) Importantly, our third model combining MSDP and NET16 showed an even larger decrease in cortical thickness in the same regions (t=3.91; 5% FDR). Secondary analyses revealed that ADHD children with homozygous genotypes (AA, TT) exposed to MSDP were significantly more severe in a specific set of externalizing symptoms. Discussion We are aiming to provide a biological link between ADHD risk factors (NET16 and MSDP), cortical thickness and behavioural/clinical outcomes. Such findings can provide insight into the pathophysiology of ADHD, as well as play a role in the transcendent process of understanding the human brain. In accordance with the literature and our previous findings, our current results hint towards an association between decreased cortical thickness in the PFC and temporal lobes and increased ADHD symptom severity. Furthermore, it has been suggested that children exposed to MSDP have a distinct ADHD phenotype and respond well to certain treatments. Therefore, our findings can help diminish clinical heterogeneity by enabling clinicians to subgroup ADHD patients with regards to MSDP exposure.