Neurodevelopmental and neurodegenerative models of schizophrenia: white matter at the center stage

Abstract

Schizophrenia is a disorder of cerebral disconnectivity whose lifetime course is modeled as both neurodevelopmental and neurodegenerative. The neurodevelopmental models attribute schizophrenia to alterations in the prenatal-to-early adolescent development. The neurodegenerative models identify progressive neurodegeneration as its core attribute. Historically, the physiology, pharmacology, and treatment targets in schizophrenia were conceptualized in terms of neurons, neurotransmitter levels, and synaptic receptors. Much of the evidence for both models was derived from studies of cortical and subcortical gray matter. We argue that the dynamics of the lifetime trajectory of white matter, and the consistency of connectivity deficits in schizophrenia, support white matter integrity as a promising phenotype to evaluate the competing evidence for and against neurodevelopmental and neurodegenerative heuristics. We develop this perspective by reviewing normal lifetime trajectories of white and gray matter changes. We highlighted the overlap between the age of peak of white matter development and the age of onset of schizophrenia and reviewed findings of white matter abnormalities prior to, at the onset, and at chronic stages of schizophrenia. We emphasized the findings of reduced white matter integrity at the onset and findings of accelerated decline in chronic stages, but the developmental trajectory that precedes the onset is largely unknown. We propose 4 probable lifetime white matter trajectory models that can be used as the basis for separation between the neurodevelopmental and neurodegenerative etiologies. We argue that a combination of the cross-sectional and longitudinal studies of white matter integrity in patients may be used to bridge the neurodevelopment and degeneration heuristics to advance schizophrenia research.

Keywords: diffusion tensor imaging; etiology of schizophrenia; white matter integrity.

Fig. 1.

Experimental (left column) and simulated (right column) life-long trajectories of fractional anisotropy (FA) and gray matter thickness (GMT) were evaluated to clarify neurodevelopmental and neurodegenerative etiologies of schizophrenia. Section (A) Normal, life-trajectories of the whole-brain average GMT (blue curve) and FA (red curve) calculated from a large cross-sectional data set of healthy subjects^, demonstrate that the peak GMT and FA values are separated by about a decade. In addition, the peak FA values overlap with the average age of the onset of psychosis. (B) Whole-brain average FA values for schizophrenia patients demonstrated significant diagnosis-by-age interaction, suggesting presence of accelerated aging in schizophrenia patients. (C) The finding of significant diagnosis-by-age interaction was replicated in an independent cohort. (D) No evidence for accelerated aging in whole-brain average GM thickness were observed in the subjects from the replication (1C) cohort (unpublished data). (E) Systematic differences in FA values across the life span would suggest the early neurodevelopmental causes of schizophrenia. (F) A shift in the age of peak in FA by 5 years in patient would also suggest an early developmental etiology and may account of finding of accelerated aging in cross-sectional samples. (H) Finally, pure neurodegenerative etiology would lead to a progressive aging-related difference in FA values.