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Background: Different regions of the brain's grey matter are connected by a complex structural network of white-matter fibres, which are responsible for the propagation of action potentials and the transport of trophic and other molecules. In neurodegenerative disease, these connections constrain the way in which grey-matter volume change progresses. Here we investigated whether connectome architecture also shapes the spatial pattern of longitudinal grey matter volume changes attributable to illness and antipsychotic medication in first episode psychosis (FEP). Methods: We conducted a triple-blind randomised placebo-control MRI study where 62 young adults with FEP received either an atypical antipsychotic or placebo over 6-months. Anatomical MRI scans were acquired at baseline, 3 months, and 12 months. Deformation-based morphometry was used to estimate illness-related and antipsychotic-related volume changes over time. Representative functional and structural brain connectivity patterns were derived from an independent healthy control group using resting-state functional MRI and diffusion-weighted imaging. We used neighbourhood deformation models to predict the extent of brain change in each of 332 parcellated areas by the changes observed in areas to which the index region is either structurally connected or functionally coupled. Results: At baseline, we found that empirical illness-related regional volume differences were robustly correlated with predicted differences using a model constrained by structural connectivity weights (r = .54; p < .001). At 3 months and 12 months, we also found a robust correlation between longitudinal regional illness-related (r > .52; p < .001) and antipsychotic-related volume change (r > .59; p < .001) with volumetric changes in structurally connected areas. These correlations were significantly greater than those observed across various null models accounting for lower-order spatial and network properties of the data. Associations between empirical and predicted volume-change estimates were much lower for models that only considered binary structural connectivity (all r < .37), or which were constrained by inter-regional functional coupling (all r < .43). Finally, we found that epicentres of volume change emerged posteriorly early in the illness and shifted to the prefrontal cortex by later illness stages. Conclusion: Psychosis- and antipsychotic-related grey-matter volume changes are strongly shaped by structural brain connectivity. This result is consistent with findings in other neurological disorders and implies that such connections may constrain pathological processes causing brain dysfunction in FEP.

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