The anatomical brain changes in first-episode schizophrenia are of interest for at least three reasons: 1) they may indicate a progression of brain changes after disease onset, 2) they may represent the core regions of pathological change in schizophrenia, and 3) they may provide a key to earlier diagnosis.
Changes in brain structure in first-episode schizophrenia have been identified by meta-analyses of MRI studies (1
). Compared with matched comparison groups, patients were found to have reduced whole brain volume (97%) and increased lateral ventricular volume (134% on the right and 125% on the left). In patients, hippocampal volumes were 92% on both sides (1
). However, amygdala volumes and temporal lobe volumes were not significantly different (3
These changes may be less widespread than those in chronic schizophrenia. Meta-analyses that included mainly patients with chronic schizophrenia (4
) found that patients also had smaller mean cerebral volumes (98%) and greater total ventricular volumes (126%). Other volumes that were smaller were the hippocampus (93% on the left and 94% on the right), the parahippocampi (92% on the left and 89% on the right), the amygdala (91% on both sides), the frontal lobes (97% on both sides), and the temporal lobes (98% on the left and 97% on the right) (5
If there are more widespread brain changes in chronic schizophrenia than in first-episode schizophrenia, then this could imply a progression of brain anatomical changes after symptom onset. Since hippocampal deficits, but not amygdala deficits, appear to be present in first-episode schizophrenia, this has led to the hypothesis that there is a progression of temporolimbic involvement after disease onset (3
). Furthermore, if there are more localized changes in first-episode schizophrenia, then these may represent the core regions of pathology (or neurodevelopmental abnormality). They may represent the critical nodes in neurochemical circuits whose continuing dysfunction leads to further anatomical changes within the circuits over time.
Finally, the identification of specific anatomical brain changes in first-episode schizophrenia could provide a key to earlier diagnosis. Studies of brain MR images in individuals at high risk of developing a psychotic disorder have found gray matter changes (7
), and it is important to define which of these changes are indicative of first-episode schizophrenia. There is some evidence that earlier diagnosis and treatment of schizophrenia lead to improved outcomes (9
In this study, we conducted meta-analyses of voxel-based morphometry imaging studies by applying the technique of activation likelihood estimation (11
). Activation likelihood estimation was originally developed to identify the brain regions that were consistently activated by a cognitive task (12
), using coordinates reported by different functional imaging studies. It assumes that although each study reported the specific coordinates of activations, technical issues (such as interindividual variability in brain anatomy) and differences in investigators’ labels for anatomical regions lead to some uncertainty as to the actual locations of these peaks. Therefore, activation foci do not represent single points but rather “localization probability distributions” centered on the particular coordinates. In activation likelihood estimation, the foci reported by each study are modeled as a probability distribution. Then a map of the whole brain is constructed, assigning to each voxel a value equal to the probability that an activation lies within the voxel. This value is called the “activation likelihood estimation.” A statistical test of these values is then performed by comparing them with values in a null distribution obtained by permutation testing, correcting for multiple comparisons by controlling the false discovery rate. For example, a false discovery rate correction guarantees that in a set of voxels deemed significant for a test of α=0.05, the expected proportion of false positives is controlled (11
One of the difficulties when comparing imaging studies is that there is considerable variability when labeling neuroanatomical regions, and differences in nomenclature could obscure findings. An advantage of the activation likelihood estimation technique is that because it uses the coordinates of reported foci (rather than anatomical labels) for meta-analysis, it avoids the problem of any mislabeling of regions in the primary literature (14
In voxel-based morphometry, MR images are analyzed for structural change at the level of voxels—the individual elements within a three-dimensional digital image (15
). This automated technique analyzes the whole brain for changes rather than selecting a subsample of regions and so may be less likely to miss changes than the more traditional region-of-interest morphometry. We call this method anatomical likelihood estimation
(ALE) when applied to voxel-based structural imaging studies, since the primary studies measure brain changes in gray matter structure rather than brain activations (as in functional imaging studies).
A previous meta-analysis of gray matter changes in schizophrenia (including mainly studies of chronic schizophrenia) found that deficits in patients were more frequently observed in various cortical and subcortical regions, including the superior temporal gyrus bilaterally, the medial frontal gyrus bilaterally, the anterior cingulate, the insular cortex bilaterally, the parahippocampal gyrus bilaterally, the thalamus, and the caudate bilaterally (17
The objectives of this meta-analysis were to use ALE to investigate gray matter structural brain changes in first-episode schizophrenia and to compare the distribution of these changes with those in chronic schizophrenia. We hypothesized that ALE analysis of first-episode schizophrenia studies would 1) identify the hippocampi but not the amygdala as regions affected by first-episode schizophrenia and 2) demonstrate more widespread cortical changes in chronic schizophrenia compared with first-episode schizophrenia.