Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study

Abstract

Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness.

Figure 1

Average brain surface contraction rates (mm per year) in control subjects (CTRL, left column), first-episode schizophrenic patients (FESZ, middle column) and the absolute difference between two groups (right column). Negative values (purple, red and yellow colors) denote surface contractions.

Figure 2

P-maps (two-tailed, uncorrected) of brain surface contraction rates and false discovery rate (FDR) maps: column 1, P-maps for control subjects (CTRL); column 2, P-maps for first-episode schizophrenic patients (FESZ); column 3, P-maps of the between-group comparison; and column 4, FDR corrected P-maps of the between-group comparison. The suprathreshold pattern of differences shown in column 3 was confirmed using permutation tests at P < 0.05 in both hemispheres, in the frontal lobe and in the superior/middle frontal gyri. As an additional test controlling for multiple comparisons, FDR (column 4) confirmed that 75% of the suprathreshold voxels on the overall cortical surface were expected to be reliable as true positives (q = 0.25, P = 0.02) and that 85% of the suprathreshold voxels in the superior/middle frontal gyri were expected to be true positives (q = 0.15, P = 0.007).

Figure 3

Brain surface contraction rates in patients who were treated with typical antipsychotics and atypical antipsychotics: (a) typical; (b) atypical; (c) absolute difference (nonsignificant in all regions).

Figure 4

Whole cortical and hemispheric bivariate distribution patterns of group-mean surface contraction for control subjects (CTRL) and first-episode schizophrenic patients (FESZ). The contours represent data point gathering across brain surface voxels at iso-density levels of smoothed distributions; the straight lines represent the first principal component through all data points. The left panel shows the bivariate distribution of the whole cortical surface, and the middle and right panels show that of the left and right hemispheres. On the hemispheric plots, the contours and first principal component lines for the frontal lobes are superimposed as gray lines on the whole hemispheric data. As the slopes of first principal component lines for all plots are close to each other, the figure shows that similar patterns of surface contractions between CTRL and FESZ were present at both global and regional levels.

Figure 5

Correlations between brain surface contraction and brain gray matter density changes: (a) correlation between cerebral gray matter volume reduction and mean brain surface contraction (R = 0.63, P < 0.001); (b) correlation between cerebral white matter volume reduction and mean brain surface contraction (R = −0.12, P = 0.57); (c) R- and P-maps showing correlation between local gray matter density reduction and surface contraction: most cerebral regions show positive correlations (that is, the greater the gray matter density reduction, the greater the surface contraction), with bilateral prefrontal, temporal pole regions and temporal–occipital conjunctions showing significant correlations.