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.

Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade

“…5 The vast majority of studies have been cross-sectional, rendering effects of specific antipsychotic compounds, transmitter systems and disease progression largely unexplored. 6,7 Two independent research groups recently proposed more comprehensive models of schizophrenia. 8,9 The models imply that disturbances in the reward system 10,11 may stem from J Psychiatry Neurosci 2016;41 (2) irregularities in myelination and subsequent delayed "corollary discharges."…”

ACNP 56th Annual Meeting: Poster Session III, December 6, 2017

“…Background: Striatal circuits support diverse affective, motor, and cognitive functions and integrate information across these domains (1). Striatal development is welldocumented into early adulthood, influencing wide-spread subcortical, cortical, and cerebellar regions, spanning a number of brain networks (2,3).…”

“…In a recent meta-analysis that examined common white matter abnormalities in emotional disorders, reduced fractional anisotropy was identified in a number of prefrontal white matter tracts (1). Very few studies have examined whether these white matter alterations.…”

“…Development of a Novel Point of Care EEG Device for Screening of Delirium patients 65 years of age or older (1)(2)(3). Delirium is, however, underdiagnosed and undertreated due to lack of effective screening instruments (4,5).…”

“…Delirium is, however, underdiagnosed and undertreated due to lack of effective screening instruments (4,5). The fact that delirium is often undetected among elderly patients admitted to the hospital leads to significantly higher mortality, longer length of stay, and higher post-discharge institutionalization rates (1)(2)(3). Along with these poorer outcomes for patients associated with delirium, the financial cost related to delirium is also immense.…”