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.

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

“…46 As we did not observe associations between DUI, negative symptoms and FA reductions (Table 3), our findings support the idea that only subtle white matter deficits in these regions are present at illness onset, but that these deficits disseminate and progress over time. 47 Our observation of FA reductions in the right CT is in line with findings in patients with early-onset schizophrenia and in individuals at high risk for psychosis. 48 However, deficits in this region are less frequently observed in later stages of illness, suggesting that FA changes in the CT may be more prominent at the time of illness onset.…”

Two Patterns of White Matter Abnormalities in Medication-Naive Patients With First-Episode Schizophrenia Revealed by Diffusion Tensor Imaging and Cluster Analysis

“…It is also worth noting that the SLF is a late-maturating tract, thus potentially more vulnerable to later neurodevelopmental disturbances during adolescence to early adulthood 50 or neurotoxic effects that take place around the onset of the first psychotic symptoms. 51 It was also noteworthy that patients with widespread and more prominent white matter abnormalities exhibited greater severity in negative symptoms than those with regional deficits. In fact, negative symptoms (ie, anhedonia, amotivation, and social dysfunction) were found to be related to specific white matter deficits in previous studies, notably with alterations in the corpus callosum, 52 uncinate, 53 SLF, 54 and ILF.…”

Diffusion Imaging of White Matter in Schizophrenia: Progress and Future Directions

“…In addition, the secondary measures of radial (RD) and axial diffusivity (AD) are believed to more specifically index myelination and axonal organization, respectively (16–18). The majority of DTI studies in schizophrenia have shown decreased FA in long-range association tracts, including the superior longitudinal fasciculus (SLF), cingulum bundle, uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF) and arcuate fasciculus (19–21). These long connection fibers likely facilitate inter-regional communication and support a wide range of cognitive abilities.…”

“…For instance, a subset of studies has shown no patient-control differences (20, 23–25), while others have found more global rather than regional effects (26–28). It is an open question whether this is a function of disease state (21), of developmental stage (29), or of another factor, such as medication. It is also possible that differences in scan acquisition, motion correction, and analysis may contribute.…”