The Balance in the Head: How Developmental Factors Explain Relationships Between Brain Asymmetries and Mental Diseases

Abstract

Cerebral lateralisation is a core organising principle of the brain that is characterised by a complex pattern of hemispheric specialisations and interhemispheric interactions. In various mental disorders, functional and/or structural hemispheric asymmetries are changed compared to healthy controls, and these alterations may contribute to the primary symptoms and cognitive impairments of a specific disorder. Since multiple genetic and epigenetic factors influence both the pathogenesis of mental illness and the development of brain asymmetries, it is likely that the neural developmental pathways overlap or are even causally intertwined, although the timing, magnitude, and direction of interactions may vary depending on the specific disorder. However, the underlying developmental steps and neuronal mechanisms are still unclear. In this review article, we briefly summarise what we know about structural, functional, and developmental relationships and outline hypothetical connections, which could be investigated in appropriate animal models. Altered cerebral asymmetries may causally contribute to the development of the structural and/or functional features of a disorder, as neural mechanisms that trigger neuropathogenesis are embedded in the asymmetrical organisation of the developing brain. Therefore, the occurrence and severity of impairments in neural processing and cognition probably cannot be understood independently of the development of the lateralised organisation of intra- and interhemispheric neuronal networks. Conversely, impaired cellular processes can also hinder favourable asymmetry development and lead to cognitive deficits in particular.

Keywords: cognitive impairment; gene environment; lateralisation; ontogeny; stress; translational/preclinical research.

Figure 1

Potential effects of asymmetry formation on the pathogenesis of a mental disorder during the three main phases of neuronal development—each phase is dominated by different cellular processes that lead to an increasingly lateralised functional organisation of the two cerebral hemispheres [179]. As a consequence, factors and processes that regulate the pathogenesis of a disorder act in a lateralised manner.

Figure 2

Simplified scheme of four possible links between the development of hemispheric asymmetries (LATERALISATION) and the pathogenesis of a mental disorder (DISORDER), based on a model proposed by Bishop [211]. While genetic factors (GENES) determine the susceptibility to the development of a particular mental disorder on the one hand and to hemispheric asymmetries on the other, it is epigenetic factors (stars), which have a decisive influence on development during different ontogenetic phases and may play a linking role between developmental pathways. The different modes of genetic–epigenetic interactions determine the properties of synaptic transmission and plasticity, as well as the structural and functional organisation of neuronal networks, leading to adaptive or maladaptive functionality and COGNITIVE EFFECTS. Not all functional consequences are related between both traits; here is only indicated how a cognitive effect results from the developmental pathways described. The direction and extent of the relationships can vary depending on the neuronal subsystems or cognitive modules and developmental phases involved.