Progressive cortical reorganisation: A framework for investigating structural changes in schizophrenia

- Progressive Grey Matter Changes (PGMC) are spatially concentrated in the topological hubs of the brain.
- PGMC are temporally concentrated in the immediate post-onset phase of schizophrenia.
- Subtle increases in GM tissue accompany PGMC in schizophrenia.
- PGMC in schizophrenia represent a remodeling response.

One of the few well-replicated features of schizophrenia is the demonstration of neuroanatomical abnormalities affecting cortical and subcortical grey matter (GM). Evidence to date suggests that the greatest reduction in GM occurs in the immediate post-onset phase. The predominant view to date is that the accelerated grey matter (GM) loss represents an adverse process (degenerative or developmental deficit) contributing to the unfavourable course of schizophrenia. This prevailing emphasis on decompensation often overlooks the fact that human brain has an inherent capacity to remodel itself in response to insults that affect its function. In the wake of emerging insights into both micro- and macro-scale brain connectivity, a substantial amount of the longitudinal structural changes seen in patients with schizophrenia could result from a distributed, nevertheless inefficient, cortical reorganization response. Quantifying cortical reorganization in the early stages of illness can enable prospective grading of the underlying pathophysiological process in schizophrenia.

The process of cortical reorganization in schizophrenia: deficiency in NMDA receptor function produces excitation-inhibition (EI) imbalance that affects the normal transmission of information across synapses, contributing to a 'bottleneck effect' at brain regions that have rich long-distance multisynaptic cortical connections (i.e. cortical hubs). Functional defects in synaptic communication convert hubs to cliques of resistance, whereby diffusion of neuronal information becomes protracted and inefficient when routed through them. The cortical reorganization seen in schizophrenia is a response to this defect. The reorganization process intends to de-escalate cortical hubs by reducing the clustering of connections around hubs - either through excitatory synaptic elimination or accelerated intracortical myelination or both. But reorganization does not restore the synaptic efficiency per se; instead, it only serves to have a 're-routing' effect, so alternate 'longer' paths of communication can now be preferentially utilised for recruiting extant regions in the service of a brain function.75