ADHD brain network during development: animal 18F-FDG PET and human fMRI study

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a complex brain developmental disorder characterized by hyperactivity/impulsivity and/or inattention. These ADHD patients are known to be defective in terms of compensation and motivation, and it is known that there is a problem in the connectivity between the prefrontal and striatum. . In addition, the suppression of the default mode network (DMN) in the ADHD brain network is not normally performed. In addition, recent advances in ADHD network analysis revealed that differences in ADHD brain network like less inhibition of default mode network (DMN) cause the brain dysfunction in ADHD. There are several hypotheses about the cause of ADHD, and the explanation that the normal maturation is delayed is supported by various studies, but the evidence for this is mainly the anatomical study on the development of cortical thickness. The main aim of this study is to evaluate the hypothesis of delayed maturation using metabolic and functional connectivity analysis. In this study, a longitudinal study of metabolic connectivity using rat 18F-FDG PET imaging and a functional connectivity cross-sectional analysis using human fMRI data were performed. SHR rats were selected as the ADHD model, WKY rats were used as controls, and 18F-FDG PET brain images were taken at 4 weeks of age (childhood) and at 6 weeks of age (entry of puberty). ADHD-200 public human fMRI data especially from Peking University was collected to compare typically developing control (TDC) and ADHD patients according to age criteria of 12 years-old. The SHR rats exhibited a variety of phenotypes. Twelve SHR rats showing distinct impulsivity and activity were selected as ADHD rats through behavior tests of marble burying test, open field test, and delay discouting task. The brain images of 12 ADHD rats and 12 control rats were analyzed. When voxel-based analysis was performed, ADHD rats and control rats were not significantly different from each other even during development from 4 weeks to 6 weeks (FWE >0.05). When the changes in the metabolic connectivity during development were evaluated using the persistent homology analysis, rat network analysis showed enhancement of the limbic (hippocampus) and cerebral cortical connections (P <0.05, permutation 10000). In ADHD rats, enhancement of the limbic (medial olfactory cortex) -cortical cortex, which was significantly weakened compared with the same 4-week-old control group, was observed during this development (P <0.05, permutation 10000). In addition, the connection between hippocampus and cerebral cortex also tended to be enhanced during ADHD development (P <0.10, permutation 10000). When the 4-week-old control group and the 6-week-old ADHD rat brain metabolic connectivity were compared, there was no significant difference in the network except for the weakening of the inter-thalamic linkage. Characteristically, during the development from 4 weeks to 6 weeks of age, ADHD rats were delayed in modulating the reward-motivation area (striatum, medial prefrontal cortex, and anterior cingulate cortex) compared to the control group. The connectivity analysis of fMRI data using persistent homology showed that the functional connectivity between children and adolescents in the TDC was significantly strengthened throughout the brain (FDR <0.05). On the other hand, the ADHD group showed localized differences of connections, and there was no significant change in the overall functional network formation pattern evaluated by the area under the curve of the barcode using persistent homology (FDR >0.05). On the other hand, there was no gross difference between the TDC group and ADHD group (FDR >0.05). Finally, we analyzed the information flow efficiency of the rat metabolic networks and the human functional networks by using volume entropy as an index. The volume entropy of the ADHD rats was lower than that of the control rats with same age. The development of ADHD rats from 4 weeks to 6 weeks of age was relatively limited but developed. When the human functional networks were analyzed, the volume entropy was significantly increased with age in the TDC group (r 0.240, P = 0.006). In contrast, the ADHD group showed no significant difference in age-related volume entropy (P >0.05). There was no statistically significant difference of volume entropy between the TDC and ADHD groups (P >0.05). In conclusion, the analysis of the metabolic network in the developmental process of the ADHD rat model revealed that delayed enhancement of the connectivity between the limbic-cerebral cortex, which partially supported the 'delayed mature hypothesis'. And the volume entropy, the overall information flow efficiency was also delayed during maturation of the ADHD rats. In the functional network study in the ADHD-200 cohort, the ADHD group showed little difference in age compared to the TDC group. A longitudinal study with appropriate medication control is needed to validate the delayed maturation hypothesis in ADHD in human data.