Childhood onset schizophrenia: support for a progressive neurodevelopmental disorder

Abstract

Structural brain abnormalities have become an established feature of schizophrenia and increasing evidence points towards the progressive nature of these abnormalities. The brain abnormalities are most profound in early onset cases, which have a severe, treatment refractory phenotype and more salient genetic features. Unique insights could thus be gained in schizophrenia pathology from studying the earliest manifestations of the illness. This paper reviews and updates the findings on anatomic brain development in patients with very early onset schizophrenia while showing preliminary data from ongoing studies. Collectively, our studies demonstrate that childhood-onset schizophrenia (COS) subjects show progressive loss of gray matter, delayed/disrupted white matter (WM) growth, and a progressive decline in cerebellar volume, some of which are shared by their healthy siblings. The developmental patterns or the 'trajectories' of brain development are often more striking than anatomic brain differences at any one point in time; highlighting the importance of longitudinal studies. The sibling findings of partially shared gray matter (GM) deficits which appear to normalize with age, along with other genetic analyses, provide evidence that the brain developmental 'patterns/trajectories' for several regions at particular ages could be useful endophenotypes (trait markers).

Fig. 1

Pattern of progression of cortical GM loss in COS. The top panel (A) shows the pattern of cortical GM loss in COS during ages 12–16. The sequence depicts p-maps across age, across entire brain surface comparing GM density at each cortical point between 12 COS children and 12 matched healthy controls repeatedly scanned between ages 12 through 16. Most significant GM loss (pink color) is visualized as a dynamic wave in the parieto-frontal direction across adolescence. The middle panel (B) shows this pattern extended up to age 24 (only shown on the right side) where the GM loss appears to decline with age and gets circumscribed to prefrontal and temporal cortices. The lower panel (C) shows areas where cortical GM loss ‘normalizes’ with age in COS; parietal and prefrontal areas showing normalization across the age range. These findings were replicated recently by using a non-overlapping sample of COS subjects and matched controls (Dr. Greenstein, unpublished data). (For interpretation of the references to color in the figure caption, the reader is referred to the web version of the article.)

Fig. 2

Diagnostic specificity of GM changes in COS. Panel A shows the parieto-frontal pattern of cortical GM loss in COS as shown in Fig. 1 earlier. Panel B shows subtle GM changes in pediatric onset psychotic bipolar I children compared with matched healthy controls. The maps are ratio maps color-coded to depict whether bipolar children have growth (yellow to orange), loss (blue to aqua) or same (green) amount of cortical GM compared to their matched controls. The patterns between COS and bipolar are non-overlapping with psychotic bipolar I subjects showing gain in temporal cortices post-onset. Panel C shows percent change in GM volume over 2-year period in matched groups of patients with atypical psychosis (MDI; blue), COS (red), and healthy control (yellow). The MDI and NV groups show no significant change over two-year period while COS shows significant GM loss. These findings, in addition to supporting the diagnostic specificity, also suggest that the GM changes in COS are unlikely to be due to medications at least at the initial scan. (For interpretation of the references to color in the figure caption, the reader is referred to the web version of the article.)

Fig. 3

Cortical GM deficits in healthy full siblings of COS. Panel A shows progression of cortical GM deficits in healthy siblings of COS patients across age. The results, published in 2007, showed early prefrontal and temporal deficits in healthy sibling compared to controls, which normalized by the time the siblings were 18 years old.

Fig. 4

White Matter growth abnormalities in COS. Comparison of 12 COS subjects with matched controls, scanned repeatedly across ages 12 through 16 showed that the WM growth was delayed for COS compared to healthy controls. Panel (A) shows absolute difference in growth rates between COS and healthy controls, while panel (B) shows significance maps for the growth difference in panel (A).