White matter development in the early stages of psychosis

Abstract

Schizophrenia has been conceptualized as a disorder of both neurodevelopment and a disorder of connectivity. One important aspect of the neurodevelopmental hypothesis is that schizophrenia is no longer thought to have discrete illness time points, but rather a long trajectory of brain changes, spanning many years, across a series of stages of the disease including the prodrome, first episode, and chronic period. As the disease progresses, there is a complex relationship between age related changes and disease related changes. Therefore, neural changes, and specifically white matter based connectivity changes, in schizophrenia may be best conceptualized based on a lifespan trajectory. In this selective review, we discuss healthy changes in white matter integrity that occur with age, as well as changes that occur across illness stages. We further propose a set of models that might explain lifespan changes in white matter integrity in schizophrenia, with the conclusion that the evidence most strongly supports a pattern of disrupted maturation during adolescence, with the potential for later changes that may be a result of disease neurotoxicity, abnormal or excessive aging effects, as well as medication, cohort or other effects. Thus, when considering white matter integrity in psychosis, it is critical to consider age in addition to other contributing factors including disease specific effects. Discovery of the factors driving healthy white matter development across the lifespan and deviations from the normal developmental trajectory may provide insights relevant to the discovery of early treatment interventions.

Keywords: Development; Diffusion tensor imaging; Prodrome; Schizophrenia; White matter.

Figure 1

Hypothesized models of developmental WM changes across the different stages of schizophrenia, compared to healthy WM changes across the lifespan. 1. Typical development: this line represents the predicted normal trajectory of white matter changes across the lifespan, with a peak in early adulthood (Peters et al., 2014; Peters et al., 2012). 2. Neurotoxic model: this line represents the trajectory according to a model in which the disease state is itself neurotoxic, resulting in white matter decline after onset. 3. Neurodevelopmental model: this model shows early alterations in the neurodevelopmental trajectory, resulting in lower white matter integrity that persists across adulthood, although the trajectory in adulthood follows a normal slope and curvature. 4. Neurodevelopmental model with later decline: this model includes both early differences in the developmental trajectory, as well as continuing decline after onset, which may be due to medication effects, disease toxicity, or an alteration in aging effects.