The interaction between genetic predisposition and environmental factors is mediated by the epigenome

An individual’s complex genetic susceptibility to a neurodevelopmental disorder is impacted by a myriad of environmental factors in intra-uterine and early life, which alter epigenomic regulation and phenotype expression.1-6

A developmental disorder is best conceptualised, applying a dynamic systems or complexity science framework, as a spectrum disorder of connectome development, that is, of the neural wiring of the brain, in which one or more feedback loops amplify small variations in early development.

Initial lesions trigger a ‘butterfly effect’ of unpredictable cascades of structural and functional imbalances in the global neuronal workspace, which dynamically interact with and impact upon the infant’s social and non-social environmental experiences, amplifying feedback loops and affecting behaviors, cognition, and social communication long-term.7

Very slight initial neural lesions may be functional or structural

The initial lesions which cause feedback loop disruptions may be structural, either genomic or due to injury; or functional, for example, from changes in the monoaminergic system. Variable phenotypic expressions emerge out of the compensations of the child’s neural networks in response to very early lesions, as myriad feedback loops in the complex adaptive system of the global neuronal workspace compensate for deficiencies and maintain the best possible functional stability. This may occur at the expense of, or with unusual development of and compensation by, higher order cognitive functions like memory, attention and executive functions. The heterogeneity of certain neurodevelopmental disorders reflect the multiple different disturbances that can occur along any one of multiple pathways. Dysregulation in any one neural or physiological pathway causes a cascade of events culminating in a cluster of symptoms.7

At the cellular level, feedback loop imbalances sculpt neuron morphology and synaptogenesis and alter synaptic transmissions by excitatory or inhibitory neurons. In the example of Autism Spectrum Disorders, by the time a child is diagnosed as neurodivergent, neuroanatomic patterns of excessive short-range connections and weakened long-range connections have emerged in vulnerable parts of the brain, including in parts of the prefrontal cortex associated with attention, social interaction, emotions, and executive control, and in a decreased density of axons below limbic cortices such as the anterior cingulate cortex.8-12

Comorbidity of neurodevelopmental disorders with other medical disorders, including neurodevelopmental, psychiatric, and physical disorders, is common, further supporting the hypothesis that impaired neural and physiological developmental cascades occur in response to very early structural or functional neural lesions. Resultant neural and physiological morbidities then interact with co-occurring behavioral morbidities.13

References

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11. Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism. The Journal of Neuroscience. 2010;30(44):14595-14609.
12. Garcia-Cabezas MA, Barbas H, Zikopoulos B. Parallel development of chromatin patterns, neuron morphology, and connections: potential for disruption in autism. Frontiers in Neuroanatomy. 2018;12(70):doi:10.3389/fnana.2018.00070.
13. Tye C, Runicles AK, Whitehouse AJO, Alvares GA. Characterizing the interplay between Autism Spectrum Disorder and comorbid medical conditions: an integrative review. Frontiers in Psychiatry. 2019;9:751.