Genetic and enviromental influence on neurocognitive and behavior development: the importance of multiple methodologies and time dependant intervention in children and adolescents with chronic and severe pathologies

Abstract

Paediatric chronic diseases are often defined by the emergence of significant neurocognitive and emotional challenges that influence the present as well as the future burden of disease. Innovative discoveries from other fields, such as, genetics and mathematical modelling together with graph analysis have led to new conceptual thinking resulting in increasingly explanatory and predictive models which offer a more realistic image of the strengths and needs of these young patients. Especially, approaches such as the research domain cluster approach and network analysis may help to improve our comprehension concerning the temporal character of the development of neurocognitive problems which is fundamental when choosing the optimal scheme for surveillance and monitor within-subject dynamic change and vulnerability over time. Does the time frame differ for different diseases, different cognitive domains or their association? Could it be that deficits in specific domains, such as, mental flexibility and the planning of an action or thought first of all depend on a deficit in a more central (hub) or earlier developing (initially more diffuse) domain of functioning? If so, therapy directed at problems related to the most central domain(s) would constitute the more rational approach because this individualized therapy automatically carries over to other domains that depend on this more central function. Epilepsy, asthma, and certain types of paediatric tumours are among the most common chronic or severe paediatric disorders. Evidence suggests that these pathologies might have a direct psychobiological link to behavioural and emotional functioning. While such comorbidities are traditionally thought to arise predominantly from the effects of recurrent clinical difficulties, iatrogenic effects of medications, and adverse psychosocial reactions to chronic or severe illness, a growing body of evidence points to the importance of genetic predisposition and environmental factors. The potential genetic, as well as the molecular pathways that might be involved include the sensitivity to context of the child or adolescent, that is, the correct functioning of the hypothalamic pituitary adrenal axis (HPA-axis). This, in combination with other genetic susceptibility factors that involve the dysregulation of a number of functional networks, such as, dopaminergic, serotoninergic, and folate related pathways, confers resilience or vulnerability to children with chronic or severe diseases with respect to the development of disease or treatment related neurocognitive or emotional and behavioural problems. Furthermore, there is a growing trend to comprehend the brain as a complex interplay of structural and functional networks. Perceiving the brain as a network provides a theoretical framework to better understand, for example, the widespread cognitive problems and structural brain abnormalities found in these diseases.