Connecting Neurobiological Features with Interregional Dysconnectivity in Social-Cognitive Impairments of Schizophrenia

Abstract

Schizophrenia (SZ) is a devastating psychiatric disorder affecting about 1% of the world's population. Social-cognitive impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social-cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the whole-brain level, an abnormal activation of social brain regions and interregional dysconnectivity within social-cognitive brain networks have been identified as major contributors to these symptoms. At the cellular and subcellular levels, an interplay between oxidative stress, neuroinflammation and N-methyl-D-aspartate receptor hypofunction is thought to underly SZ pathology. However, it is not clear how these molecular processes are linked with interregional dysconnectivity in the genesis of social-cognitive symptoms. Here, we aim to bridge the gap between macroscale (connectivity analyses) and microscale (molecular and cellular mechanistic) knowledge by proposing impaired myelination and the disinhibition of local microcircuits as possible causative biological pathways leading to dysconnectivity and abnormal activity of the social brain. Furthermore, we recommend electroencephalography as a promising translational technique that can foster pre-clinical drug development and discuss attractive drug targets for the treatment of social-cognitive symptoms in SZ.

Keywords: N-methyl-D-aspartate receptor; functional connectivity/dysconnectivity; inflammation; oxidative stress; schizophrenia; social cognition; structural connectivity/dysconnectivity.

Figure 1

Schematic representation of the deleterious effects of neurobiological processes involved in schizophrenia on WM tracts supporting social-cognitive networks; example of altered PFC-AMY connectivity. Oxidative stress, neuroinflammation and NMDA receptor hypofunction may damage WM by reducing myelination and inducing oligodendrocyte (OL) death, for instance at the level of the uncinate fasciculus and cingulum that both allow connections between the social-brain regions PFC and AMY. This mechanism may also occur within social brain regions (e.g., PFC) and at the whole social-brain level and may consequently impact social cognition and associated behaviors.

Figure 2

Chart summarizing the proposed link between micro- and macroscale factors involved in the development of social-cognitive symptoms of schizophrenia.