Maturational delay and asymmetric information flow of brain connectivity in SHR model of ADHD revealed by topological analysis of metabolic networks

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a complex brain development disorder characterized by hyperactivity/impulsivity and inattention. A major hypothesis of ADHD is a lag of maturation, which is supported mainly by anatomical studies evaluating cortical thickness. Here, we analyzed changes of topological characteristics of whole-brain metabolic connectivity in twelve SHR rats selected as ADHDmodel rats by confirming behavior abnormalities using the marble burying test, open field test, and delay discounting task and 12 Wistar Kyoto rats as the control group, across development from 4 weeks old (childhood) and 6 weeks old (entry of puberty). A topological approach based on graph filtrations revealed a lag in the strengthening of limbic-cortical/subcortical connections in ADHD-model rats. This in turn related to impaired modularization of memory and reward-motivation associated regions. Using mathematical network analysis techniques such as single linkage hierarchical clustering and volume entropy, we observed left-lateralized connectivity in the ADHD-model rats at 6 weeks old. Our findings supported the maturational delay of metabolic connectivity in the SHR model of ADHD, and also suggested the possibility of impaired and compensative reconfiguration of information flow over the brain network. Attention-deficit hyperactivity disorder (ADHD) is one of the most common brain developmental disorder characterized by typical symptoms of inattention, hyperactivity, and impulsivity. ADHD patients have not only problems with attention and executive function but also suffer from considerable memory impairment, especially for working memory and even long-term memory 1,2. ADHD usually initiates during childhood or school-age 3. Almost 35% of ADHD subjects become symptom-free within adolescence 4. About the pathogenesis of ADHD, there has been controversy about whether ADHD is caused by permanent deviation from typical brain development or delayed normal maturation of the brain. The delayed maturation hypothesis was supported by structural

Lifespan associations of resting-state brain functional networks with ADHD symptoms

“…Children/adolescents (7.2–21.8 years) with ADHD were found to have a functional maturation lag in the DMN ( Sripada et al., 2014b ), and young ADHD rats (4–6 weeks) had a lag in limbic regions ( Ha et al., 2020 ). Here, we found that the limbic system dominantly affected by ADHD can better predict hyperactivity in ADHD patients, but not in HCs.…”

Impaired Local and Long-Range Brain Connectivity and Visual Response in a Genetic Rat Model of Hyperactivity Revealed by Functional Ultrasound

“…This animal model exhibits the behavioral characteristics of the disorder ( Sagvolden, 2000 ) and displays several variations in the Dat1 gene encoding the dopamine transporter ( Mill et al, 2005 ), known to be related to ADHD ( Cook et al, 1995 ; Faraone et al, 2005 ; Madras et al, 2005 ). Finally, conventional neuroimaging studies have shown structural and functional alterations in SHR rats similar to those observed in ADHD ( Danker and Duong, 2007 ; Huang et al, 2016 ; Ha et al, 2020 ).…”

Improvement of Pursuit Eye Movement Alterations after Short Visuo-Attentional Training in ADHD

“…Given the several cortical and sub-cortical structures implicated in pursuit triggering [24], the absence of a developmental effect on pursuit performances in children with ADHD could be due to a shift of maturation processes (immaturity) of the areas involved in pursuit eye movements. A major hypothesis of ADHD suggested a lag of maturation of brain structures, which is supported mainly by anatomical studies evaluating cortical thickness [25]. These anatomical studies could explain the hypothesis on the immaturity of cortical structures responsible for pursuit triggering.…”